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Traumatic heterotopic ossification (HO) of the lower extremity is relatively rare but is of major importance in clinical practice. They are defined as posttraumatic abnormal formations of bone within soft tissue outside of the skeletal system. This article describes the clinical case of a 31-year-old male patient who suffered 2 traumatic events within 12 months—a gunshot wound in the lumbar spine/gluteal region followed by a severe traumatic brain injury with intracranial hemorrhage in a traffic accident as a pedestrian. Clinically, the patient was bedridden because of complete stiffening of the lumbar spine, both hip joints, and the left knee joint. After preoperative diagnosis, 3 surgical ablations of the HO were performed on both the hip joints and the left knee joint. In addition, physiotherapeutic exercise, postoperative nonsteroidal anti-inflammatory drug administration (25 mg of indomethazine for 6 weeks, 3 times a day), and perioperative radiation with 7 Gy for each operation were advised. After 4 years of follow-up, the patient showed significant improvement. In HO treatment, prophylactic local radiotherapy (pre- and postoperative radiation with a local single dose of 7 Gy) and postoperative administration of nonsteroidal anti-inflammatory drugs are often recommended. For therapeutic purposes, surgical resection is still indicated for pronounced cases. [ABSTRACT FROM AUTHOR]

Global use of dexamethasone in COVID-19 patients has revealed a poor understanding of the drug-drug interaction (DDI) potential of dexamethasone, particularly with antiretroviral agents (ARVs). Dexamethasone is both a substrate and a dose-dependent inducer of cytochrome P450 3A4 (CYP3A4). As many ARVs are substrates and/or inhibitors or inducers of CYP3A4, there is concern about DDIs with dexamethasone either as a perpetrator or a victim. Assessment of DDIs that involve dexamethasone is complex as dexamethasone is used at a range of daily doses (generally 0.5 up to 40 mg) and a treatment course can be short, long, or intermittent. Moreover, DDIs with dexamethasone have been evaluated only for a limited number of drugs. Here, we summarize the available in vitro and in vivo data on the interaction potential of dexamethasone and provide recommendations for the management of DDIs with ARVs, considering various dexamethasone dosages and treatment durations. [ABSTRACT FROM AUTHOR]

As global health services respond to the coronavirus pandemic, many prescribers are turning to experimental drugs. This review aims to assess the risk of drug-drug interactions in the severely ill COVID-19 patient. Experimental therapies were identified by searching ClinicalTrials.gov for 'COVID-19', '2019-nCoV', '2019 novel coronavirus' and 'SARS-CoV-2'. The last search was performed on 30 June 2020. Herbal medicines, blood-derived products and in vitro studies were excluded. We identified comorbidities by searching PubMed for the MeSH terms 'COVID-19', 'Comorbidity' and 'Epidemiological Factors'. Potential drug-drug interactions were evaluated according to known pharmacokinetics, overlapping toxicities and QT risk. Drug-drug interactions were graded GREEN and YELLOW: no clinically significant interaction; AMBER: caution; RED: serious risk. A total of 2378 records were retrieved from ClinicalTrials.gov, which yielded 249 drugs that met inclusion criteria. Thirteen primary compounds were screened against 512 comedications. A full database of these interactions is available at www.covid19-druginteractions.org. Experimental therapies for COVID-19 present a risk of drug-drug interactions, with lopinavir/ritonavir (10% RED, 41% AMBER; mainly a perpetrator of pharmacokinetic interactions but also risk of QT prolongation particularly when given with concomitant drugs that can prolong QT), chloroquine and hydroxychloroquine (both 7% RED and 27% AMBER, victims of some interactions due to metabolic profile but also perpetrators of QT prolongation) posing the greatest risk. With management, these risks can be mitigated. We have published a drug-drug interaction resource to facilitate medication review for the critically ill patient. [ABSTRACT FROM AUTHOR]

Background: Cabotegravir and rilpivirine are 2 long-acting (LA) antiretrovirals that can be administered intramuscularly; their interaction with rifampicin, a first-line antituberculosis agent, has not been investigated. The aim of this study was to simulate and predict drug-drug interactions (DDIs) between these LA antiretroviral agents and rifampicin using physiologically based pharmacokinetic (PBPK) modeling.Methods: The designed PBPK models were qualified (according to European Medicines Agency guidelines) against observed data for oral formulations of cabotegravir, rilpivirine, and rifampicin. Induction potential of rifampicin was also qualified by comparing the DDI between oral cabotegravir and oral rilpivirine with rifampicin. Qualified PBPK models were utilized for pharmacokinetic prediction of DDIs.Results: PBPK models predicted a reduction in both area under the curve (AUC0-28 days) and trough concentration (Ctrough, 28th day) of LA cabotegravir of 41%-46% for the first maintenance dose coadministered with 600 mg once-daily oral rifampicin. Rilpivirine concentrations were predicted to decrease by 82% for both AUC0-28 days and Ctrough, 28th day following the first maintenance dose when coadministered with rifampicin.Conclusions: The developed PBPK models predicted the theoretical effect of rifampicin on cabotegravir and rilpivirine LA intramuscular formulations. According to these simulations, it is likely that coadministration of rifampicin with these LA formulations will result in subtherapeutic concentrations of both drugs. [ABSTRACT FROM AUTHOR]

Introduction: Modern health systems have to respond to a wide variety of catastrophic scenarios, from natural disasters to terror attacks. It is reasonable to already start educational approaches for physicians in this field at medical school level. An approach combining civilian disaster medicine and military deployment medicine can be beneficial both for clinical strategies and in undergraduate teaching.Materials and Methods: A curricular 4-week teaching module on "deployment and disaster medicine," interdisciplinarily combining over 12 medical specialties, was launched in the summer semester of 2016 at a civilian medical school. The course was integrated into the undergraduate curriculum by learning spirals. Teaching formats encompassed a total of 72 hours of seminars, clinical case discussions, group work, e-Learning, and practical training. The students' gain in knowledge was analyzed with pre/post-multiple-choice tests and their attitude towards the offer was evaluated.Results: A total of 51 students participated in the module over three semesters. The evaluation revealed that the students were highly satisfied with the offer and felt motivated to increase their engagement with the topic. The students additionally valued the course as a good means of deepening the core curriculum. The pre/post-tests showed a significant gain in knowledge among the students (p < 0.001).Conclusions: The course presented received an overall highly positive feedback from the participating students. The experience of this approach suggests that the combination of civilian and military knowledge and expertise in deployment and disaster medicine may lead to the creation of effective interdisciplinary course concepts. [ABSTRACT FROM AUTHOR]

The development of therapeutic agents against SARS-CoV-2/COVID-19  faces numerous barriers and a multidisciplinary approach to evaluating drug efficacy and toxicity is essential. Experimental and preclinical data should be integrated into a comprehensive analysis, where drug potency, the timing of therapy initiation, drug combinations, variability in systemic and local drug exposure and short- and long-term toxicities represent fundamental factors for the rational identification of candidates and prioritization of clinical investigations. Although the identification of SARS-CoV-2 therapeutics is a priority, rigorous and transparent methodologies are crucial to ensure that accelerated research programmes result in high-quality and reproducible findings. [ABSTRACT FROM AUTHOR]

Background: HIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low levonorgestrel exposure and unintended pregnancy.Objectives: To investigate clinically applicable dose-adjustment strategies to overcome the known drug-drug interaction (DDI) between levonorgestrel and efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach.Methods: A PBPK model was qualified against clinical data to predict levonorgestrel plasma concentrations when standard-dose (150 mg) levonorgestrel implants were administered alone (control group), as well as when standard-dose or increased-dose (300 mg) levonorgestrel implants were coadministered with either 600 or 400 mg of efavirenz.Results: No difference was seen between in vivo clinical and PBPK-model-simulated levonorgestrel plasma concentrations (P > 0.05). Simulated levonorgestrel plasma concentrations were ∼50% lower at 48 weeks post-implant-placement in virtual individuals receiving standard-dose levonorgestrel with either 600 or 400 mg of efavirenz compared with the control group (efavirenz:control geometric mean ratio = 0.42 and 0.49, respectively). Conversely, increased-dose levonorgestrel in combination with either 600 or 400 mg of efavirenz was sufficient to restore levonorgestrel concentrations to levels similar to those observed in the 150 mg levonorgestrel control group 48 weeks post-implant-placement (efavirenz:control geometric mean ratio = 0.86 and 1.03, respectively).Conclusions: These results suggest that the clinically significant DDI between efavirenz and levonorgestrel is likely to persist despite efavirenz dose reduction, whereas dose escalation of implantable levonorgestrel may represent a successful clinical strategy to circumvent efavirenz-levonorgestrel DDIs and will be of use to inform clinical trial design to assess coadministration of efavirenz and levonorgestrel implants. [ABSTRACT FROM AUTHOR]

Background: Co-administration of antineoplastics with ART is challenging due to potential drug-drug interactions (DDIs). However, trials specifically assessing such DDIs are lacking. Our objective was to simulate DDIs between the antineoplastics erlotinib and gefitinib with key antiretroviral drugs and to predict dose adjustments using a physiologically based pharmacokinetic (PBPK) model.Methods: In vitro data describing chemical properties and pharmacokinetic processes of each drug and their effect on cytochrome P450 isoforms were obtained from the literature. Plasma drug-concentration profiles were simulated in a virtual population of 50 individuals receiving erlotinib or gefitinib alone or with darunavir/ritonavir, efavirenz or etravirine. Simulated pharmacokinetic parameters and the magnitude of DDIs with probe drugs (midazolam, maraviroc) were compared with literature values. Erlotinib and gefitinib pharmacokinetics with and without antiretrovirals were compared and dose-adjustment strategies were evaluated.Results: Simulated parameters of each drug and the magnitude of DDIs with probe drugs were in agreement with reference values. Darunavir/ritonavir increased erlotinib and gefitinib exposure, while efavirenz and etravirine decreased erlotinib and gefitinib concentrations. Based on our predictions, dose-adjustment strategies may consist of once-daily dosing erlotinib at 25 mg and gefitinib at 125 mg with darunavir/ritonavir; or erlotinib at 200 mg and gefitinib at 375 mg with etravirine. The interaction with efavirenz was not overcome even after doubling erlotinib or gefitinib doses.Conclusions: PBPK models predicted the in vivo pharmacokinetics of erlotinib, gefitinib and the antiretrovirals darunavir/ritonavir, efavirenz and etravirine, and the DDIs between them. The simulated dose-adjustments may represent valuable strategies to optimize antineoplastic therapy in HIV-infected patients. [ABSTRACT FROM AUTHOR]

Nearly all HIV PIs and the integrase inhibitor elvitegravir require a pharmacokinetic enhancer in order to achieve therapeutic plasma concentrations at the desired dose and frequency. Whereas ritonavir has been the only available pharmacokinetic enhancer for more than a decade, cobicistat has recently emerged as an alternative boosting agent. Cobicistat and ritonavir are equally strong inhibitors of cytochrome P450 (CYP) 3A4 and consequently were shown to be equivalent pharmacokinetic enhancers for elvitegravir and for the PIs atazanavir and darunavir. Since cobicistat is a more selective CYP inhibitor than ritonavir and is devoid of enzyme-inducing properties, differences are expected in their interaction profiles with some co-medications. Drugs whose exposure might be altered by ritonavir but unaltered by cobicistat are drugs primarily metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 or drugs undergoing mainly glucuronidation. Thus, co-medications should be systematically reviewed when switching the pharmacokinetic enhancer to anticipate potential dosage adjustments. [ABSTRACT FROM AUTHOR]

Objectives: Treatment of HIV/TB coinfection is challenging due to potent drug-drug interactions between antiretrovirals and rifampicin. The effect of rifampicin on darunavir/ritonavir has not been studied. Population pharmacokinetic modelling was applied to investigate the interaction and generate alternative doses to inform clinical trial design.Patients and Methods: Darunavir/ritonavir concentrations were modelled simultaneously, including data from three studies in HIV patients (n = 51, 7 female). The darunavir/ritonavir-rifampicin interaction was assumed to mimic that previously observed with lopinavir/ritonavir. Daily darunavir/ritonavir 800/100 mg was simulated as a reference (n = 1000; -rifampicin). Simulations with apparent oral clearance increased by 71% and 36% and relative bioavailability decreased by 20% and 45% for darunavir and ritonavir, respectively, were performed for +rifampicin, 600 mg once daily (n = 1000). Darunavir/ritonavir 1200/200 mg once daily, 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily +rifampicin were simulated. Darunavir parameters for each dose +rifampicin were compared with -rifampicin by geometric mean ratio (90% CI).Results: A maximum effect model, with ritonavir inhibiting darunavir clearance, best described the relationship between the drugs. Compared with -rifampicin, simulated darunavir AUC0-24 was 57%, 26%, 1% and 16% lower for 800/100 mg once daily, 1200/200 mg once daily, 1600/200 mg once daily and 800/100 mg twice daily +rifampicin, respectively; but 39% higher with 1200/150 mg twice daily +rifampicin.Conclusions: Darunavir/ritonavir 1600/200 mg once daily, 800/100 mg twice daily and 1200/150 mg twice daily could potentially overcome reduced darunavir concentrations with rifampicin. In the absence of clinical data, modelling and simulation may be useful to predict drug-drug interactions and aid optimal dose selection. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate dolutegravir and elvitegravir/cobicistat pharmacokinetics in HIV-negative volunteers up to 10 days after drug cessation.Methods: Healthy volunteers received 50 mg of dolutegravir once-daily for 10 days, then underwent a 9 day wash-out period, and then received elvitegravir/cobicistat as part of Stribild(®) (245 mg of tenofovir, 200 mg of emtricitabine, 150 mg of elvitegravir and 150 mg of cobicistat) for 10 days. Serial pharmacokinetic (PK) sampling occurred prior to the final dose of each course and at regular intervals for up to 216 h (10 days) after drug cessation. Concentrations were determined by LC-MS/MS, and PK parameters were illustrated as geometric mean and 90% CI.Results: Seventeen volunteers completed the study. For dolutegravir, plasma terminal elimination t1/2 to the last measurable concentration (within 216 h) was longer than its t1/2 within the dosing interval (0-24 h): 14.3 h (12.9-15.7 h) versus 23.1 h (19.7-26.6 h); conversely, the terminal elimination t1/2 for elvitegravir was lower than its t1/2 within the dosing interval (0-24 h): 10.8 h (9.7-13.0 h) versus 5.2 h (4.7-6.1 h). Dolutegravir concentrations were above the protein-adjusted (PA) IC90 (64 ng/mL) in 100% of subjects after 36 and 48 h and in 94% after 60 and 72 h. All subjects had detectable dolutegravir concentrations at 96 h, a mean of 23.5% above the IC90. Elvitegravir concentrations were above the PA IC95 (45 ng/mL) in 100% of subjects at 24 h, 65% at 36 h but 0% after 48 h.Conclusions: Our data show marked differences in the elimination rates of dolutegravir and elvitegravir following treatment interruption, which is likely to impact the extent to which drug doses can be delayed or missed. They suggest that clinical differences may emerge in patients who have suboptimal adherence. [ABSTRACT FROM AUTHOR]

Background. Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics. Methods. This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies. Results. Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43).Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups. Conclusions. Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz- based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy. [ABSTRACT FROM AUTHOR]

The injectable long-acting formulation of rilpivirine (TMC278LA) is a promising preexposure prophylaxis (PrEP) candidate for prevention of human immunodeficiency virus type 1 (HIV-1) infection. We evaluated HIV-1 in plasma obtained from an unexpected seroconverter in the 300-mg arm of the SSAT040 TMC278LA pharmacokinetic study for rilpivirine (RPV) resistance. Infection with wild-type HIV-1 was confirmed on day 84 after TMC278LA injection, and the K101E mutation was detected on day 115. Plasma-derived HIV-1 clones containing K101E had 4-fold increased resistance to RPV and 4-8-fold increased cross-resistance to etravirine, nevirapine, and efavirenz compared with wild type HIV-1 plasma-derived clones from the same individual. This case is a unique instance of infection with wild-type HIV-1 and subsequent selection of resistant virus by persistent exposure to long-acting PrEP. [ABSTRACT FROM AUTHOR]

Background. With the approval of direct-acting antivirals (DAAs), the management of drug-drug interactions (DDIs) has become an important challenge while treating individuals with hepatitis C. To date, the potential of causing DDIs for the recently approved DAAs has not been systematically investigated. We aimed to assess the clinical significance of DDI between the regular outpatient medications and DAA therapies in a large real-world cohort. Methods. Overall, 261 hepatitis C virus monoinfected patients who were selected for DAA therapy at 2 intervals between 2011 and 2014 were asked about their regular outpatient medications. The potential for DDIs between all these drugs and sofosbuvir/ribavirin, ledipasvir/sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir as well as boceprevir and telaprevir triple therapy was assessed using www.hep-druginteractions.org and the relevant prescribing information. Results. The 261 patients took a median number of 2 drugs (range 0-15); 20% of patients did not take any medication. Sofosbuvir/ ribavirin had the lowest risk to cause a potentially significant DDI (9.6%). In contrast, for ombitasvir/paritaprevir/ritonavir ± dasabuvir potentially significant DDIs could be expected in 66.3% of the patients. Significant DDIs for sofosbuvir/simeprevir would be expected in 31.4%, for sofosbuvir/daclatasvir in 36.8%, and for sofosbuvir/ledipasvir in 40.2%. Proton pump inhibitors, thyroid hormones, and dihydropyridine derivatives were frequently used and presented a risk of interacting with the antiviral regimen. Conclusions. A significant number of patients are at risk for DDIs if treated with the recently approved DAA regimens. A careful evaluation of potential DDI is essential to prevent adverse effects or unnecessary risk of treatment failure. [ABSTRACT FROM AUTHOR]

Objectives: The validation and clinical application of an LC-MS/MS method for the quantification of nevirapine in dried blood spots (DBS) and dried breast-milk spots (DBMS) are presented.Methods: DBS and DBMS were prepared from 50 and 30 μL of nevirapine-spiked whole blood and human breast milk, respectively. Chromatographic separation was achieved on a reverse-phase C18 column with 0.1% formic acid in water/acetonitrile using a solvent gradient programme at a flow rate of 400 μL/min, and detection was by a TSQ Quantum Access triple quadrupole mass spectrometer. The clinical application was evaluated in HIV-positive nursing mothers and their breastfed infants.Results: The assay was validated over the concentration range 50-10,000 ng/mL. Accuracy ranged from 93.3% to 113.4% and precision ranged from 1.9% to 12.0%. The mean (percentage coefficient of variation) recovery of nevirapine from DBS and DBMS was ≥ 70.7% (≤ 8.2) and the matrix effect was ≤ 1.04 (≤ 6.1). Nevirapine was stable in DBS and DBMS for ≥ 15 months at room temperature and -80°C. Mean (SD) AUC0-12, Cmax and Cmin in maternal plasma versus breast milk were 57,808 ng · h/mL (24,315) versus 55,817 ng · h/mL (22,368), 6140 ng/mL (2605) versus 5231 ng/mL (2215) and 4334 ng/mL (1880) versus 4342 ng/mL (2245), respectively. The milk-to-plasma concentration ratio over the dosing interval was 0.94 (0.15). Infant plasma concentrations 2 and 8 h after maternal dosing were 580.6 ng/mL (464.7-1607) and 584.1 ng/mL (381.5-1570), respectively.Conclusions: These methods further extend opportunities for conducting clinical pharmacokinetic studies in nursing mother-infant pairs, especially in resource-limited settings. [ABSTRACT FROM AUTHOR]

Background. The antiretroviral drug efavirenz is widely used during breastfeeding. Evaluating its safety requires an understanding of its breast milk pharmacokinetics, level of breastfed infants' exposure, and potential influence of polymorphisms in drug disposition genes. Methods. For this observational study, we investigated plasma and breast milk pharmacokinetics of efavirenz and breastfed infants' exposure in human immunodeficiency virus positive nursing mothers and their breastfed infants. We also evaluated potential variability due to genetic polymorphisms in CYP2B6, NR1I3, CYP2A6, ABCB1, ABCB5, and ABCG2. Results. CYP2B6 516G>T was independently associated with efavirenz concentrations in maternal plasma, breast milk, and infant plasma (n = 134). When stratified based on CYP2B6 516G>T (n = 29 ; 11 GG, 10 GT and 8 TT), efavirenz pharmacokinetic parameters in plasma and breast milk differed significantly between patient groups. The median time-averaged milk-to-plasma concentration ratio was 1.10 (range: 0.57-1.71). The estimated maximum infant efavirenz dose from breast milk was 809 µg/kg/day (215-2760) and pediatric dose weight-adjusted exposure index was 4.05% (1.08-13.8). Infant plasma concentrations did not change significantly during the dosing interval, 157 ng/mL (28.6-1360) in pooled analysis and 315 ng/mL (108-1360) in CYP2B6 516TT group. Infant plasma concentrations were highest up to 8 days of age at 1590 ng/mL (190-4631) and decreased by about 90% in the age stratum day 9 to 3 months. No efavirenz related toxicity was reported. Conclusions. Most breastfed infants are exposed to <10% of the weight-adjusted therapeutic pediatric dose, the safety threshold for exposure to maternal drugs from breast milk. [ABSTRACT FROM AUTHOR]

Objectives: Boceprevir is a first-generation direct-acting antiviral licensed for the treatment of hepatitis C infection. Sildenafil is an oral therapy for erectile dysfunction. As boceprevir is a potent inhibitor of CYP3A4, potential pharmacokinetic interactions may occur when it is coadministered with sildenafil. The aim of this study was to assess the pharmacokinetic profile of sildenafil and boceprevir when dosed separately and together in healthy volunteers. Methods: Thirteen male subjects completed the following study procedures: phase 1 (Day 0), a single dose of 25 mg of sildenafil was administered; washout period (Days 1-9); phase 2 (Days 10-15), 800 mg of boceprevir three times a day was administered; and phase 3 (Day 16), 800 mg of boceprevir and 25 mg of sildenafil were administered. All drugs were administered in the fed state. Intensive pharmacokinetic sampling was undertaken on Days 0, 15 and 16. Differences in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and boceprevir between phase 3 and the earlier phases were evaluated by changes in the geometric mean ratios (GMRs). Results: All the drugs were well tolerated with no safety concerns arising. In the presence of boceprevir (phase 3 versus phase 1), the GMR for the plasma Cmax and the AUC24 for sildenafil increased by 1.9-fold (95% CI 1.5-2.4) and 2.7-fold (95% CI 2.1-3.4), respectively, whereas a reduction in the Cmax of N-desmethyl-sildenafil was observed (GMR 0.5, 95% CI 0.4-0.7). No significant changes in boceprevir exposure were observed between phases 3 and 2. Conclusions: Exposure of sildenafil is increased in the presence of boceprevir. A dose adjustment of sildenafil is therefore necessary. An initial dose of 25 mg of sildenafil is suggested. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to assess whether a lower dose than the currently used one of darunavir/ ritonavir might achieve good CSF concentrations and contribute to inhibition of CNS viral replication. Patients and methods: This was a substudy of a randomized, open, multicentre study (eudraCT 2011-006272- 39), comparing the efficacy and safety of 800/100 mg of darunavir/ritonavir (darunavir 800) versus 600/100 mg of darunavir/ritonavir (darunavir 600) once daily plus tenofovir/emtricitabine or abacavir/lamivudine in 100 virologically suppressed patients. Paired blood and CSF samples were obtained. Total plasma darunavir concentrations were determined by HPLC, and CSF concentrations by liquid chromatography-tandem MS. Viral load (VL) was determined in plasma and CSF (limit of detection = 40 copies/mL) by PCR. Results: Sixteen patients were enrolled. The median (range) of darunavir CSF concentrations in darunavir 600 (n = 8) and darunavir 800 (n = 8) patients was 17.08 (5.79-30.19) and 13.23 (3.47-32.98) ng/mL, respectively (P = 0.916). The median (range) darunavir CSF:plasma ratio was 0.010 (0.005-0.022) in darunavir 600 patients and 0.008 (0.004-0.017) in the darunavir 800 arm (P = 0.370). All 16 patients had a VL<40 copies/mL in plasma and 14 had a VL < 40 copies/mL in CSF. Of the two patients with detectable CSF VL (280 copies/mL and 159 copies/mL), one was receiving darunavir 600 and the other darunavir 800 plus tenofovir/emtricitabine. Of note, these patients had the lowest CSF darunavir concentrations in their respective groups: 5.79 ng/mL (802 ng/mL in plasma) and 3.47 ng/mL (958 ng/mL in plasma). Conclusions: Darunavir CSF and plasma concentrations were comparable between the two arms. However, one patient from each group (with the lowest CSF darunavir concentrations in their respective groups) had detectable CSF VL despite undetectable plasma VL. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effect of food on the steady-state pharmacokinetics of rilpivirine when administered as a fixed-dose combination tablet containing tenofovir disoproxil fumarate, emtricitabine plus rilpivirine (TDF/FTC/RPV) in HIV-1-infected Ugandan patients. Methods: This was an open-label, three-period, longitudinal pharmacokinetic study with patients serving as their own controls. Fifteen consenting and virologically suppressed HIV-1-infected adults were switched from an efavirenz-based regimen to TDF/FTC/RPV for 56 days. Enrolled patients underwent 24 h blood sampling with TDF/FTC/RPV dosing in the fasted state (day 42), with a low-fat meal (11 g of fat/353 kcal, day 49) and with a moderate-fat meal (19 g of fat/589 kcal, day 56; reference). A viral load assessment was performed on day 56. Results: Rilpivirine AUC0-24 was significantly decreased by 16% (geometric mean ratio, 90% CI: 0.84, 0.73-0.96) during administration in the fasted state when compared with AUC0-24 during administration with a moderate-fat meal. Similarly, rilpivirine C24 was significantly decreased by 21% (0.79, 0.65-0.97) in the fasted state compared with a moderate-fat meal. Pharmacokinetic parameters were unchanged during administration with a low-fat meal, except for C24, which was significantly increased by 15% (1.15, 1.01-1.31) when compared with the moderate-fat meal. Rilpivirine Cmax was similar under the three meal conditions. Virological suppression was unchanged at the end of the study. Conclusions: A food effect was observed for steady-state pharmacokinetic parameters of rilpivirine (AUC0-24 and C24) when TDF/FTC/RPV was administered in the fasted state compared with the moderate-fat meal. The TDF/FTC/RPV formulation can be administered with either a low-fat or moderate-fat meal. [ABSTRACT FROM AUTHOR]

Objectives: This manuscript describes the development, validation and clinical application of a novel method for the quantification of the antiretroviral drug efavirenz in dried breast milk spots using LC-MS.Methods: Dried breast milk spots were prepared by spotting 30 μL of human breast milk on each circle of Whatman 903 Protein Saver cards. Chromatographic separation was achieved on a reverse-phase C18 column with 1 mM ammonium acetate in water/acetonitrile using a solvent gradient at a flow rate of 400 μL/min and detection was by TSQ Quantum Access triple quadrupole mass spectrometer equipped with a heated electrospray ionization source. The method was applied to characterize the breast milk pharmacokinetic profile of efavirenz in HIV-positive nursing mothers receiving regimens containing 600 mg of efavirenz once daily.Results: The assay was validated over the concentration range 50-7500 ng/mL. Accuracy ranged between 95.2% and 102.5% and precision ranged between 1.05% and 9.53%. The average recovery of efavirenz from dried breast milk spots was 106.4% and the matrix effect was 8.14%. Stability of efavirenz in dried breast milk spots and processed samples at room temperature, -40°C and -80°C was demonstrated. In the pharmacokinetic study, the mean (SD) AUC0-24, Cmax and Cmin of efavirenz in breast milk were 59,620 ng·h/mL (17,440), 4527 ng/mL (1767) and 1261 ng/mL (755.9), respectively. The mean (range) milk-to-plasma concentration ratio over the dosing interval was 0.78 (0.57-1.26).Conclusions: The dried breast milk spot method is simple, robust, accurate and precise, and can be used in settings with limited resources. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies of raltegravir and rifampicin have not studied the interaction when rifampicin is dosed intermittently. This study aimed to assess the pharmacokinetics of twice daily raltegravir and intermittently dosed rifampicin.Methods: This was a prospective, open, single-arm, three-part, controlled study in healthy volunteers. Over a period of 38 days subjects received 5 days of standard-dose raltegravir (400 mg twice daily) followed by 28 days of standard-dose raltegravir plus rifampicin three times a week followed by 5 days of high-dose (800 mg twice daily) raltegravir plus rifampicin three times a week. Pharmacokinetic sampling was performed on days 5, 33 and 38. Raltegravir pharmacokinetic parameters were determined by non-compartmental analysis and reported as geometric means and 90% CIs. ClinicalTrials.gov: NCT01424826.Results: Sixteen subjects (12 females) completed the study. Raltegravir trough plasma concentration (C12) was significantly lower in the presence of rifampicin when dosed at 400 mg twice daily (40%), which was not observed with 800 mg twice daily dosing. Raltegravir Cmax and AUC0-12 were both significantly higher in the presence of rifampicin when dosed at 800 mg twice daily (76% and 84%, respectively), but this dose was well tolerated.Conclusions: This study suggests that rifampicin induction of raltegravir is comparable between daily and intermittent rifampicin. In the absence of definitive clinical efficacy data to suggest otherwise, doses of 800 mg of raltegravir twice daily with rifampicin thrice weekly are well tolerated and yield higher AUCs and comparable C12 when compared with raltegravir alone. [ABSTRACT FROM AUTHOR]

Objectives Pharmacokinetic parameters following modifications to antiretroviral therapy and sanctuary site exposure are often unknown for recently licensed antiretrovirals. We assessed plasma, CSF and seminal plasma (SP) exposure of rilpivirine after switching from nevirapine. Methods HIV-infected male subjects receiving tenofovir/emtricitabine/nevirapine (245/200/400 mg) once daily switched to tenofovir/emtricitabine/rilpivirine (245/200/25 mg) once daily for 60 days when CSF and semen samples were collected. Mean and individual plasma concentrations of nevirapine and rilpivirine were compared with the proposed plasma target concentration for nevirapine (3000 ng/mL) and the protein binding-adjusted EC90 for rilpivirine (12.1 ng/mL). Mean rilpivirine CSF and SP concentrations were calculated and individual values compared with the EC50 and EC90 for wild-type virus (0.27 and 0.66 ng/mL, respectively). Results Of 13 subjects completing study procedures including CSF examination, 8 provided seminal samples. By day 3, the mean plasma rilpivirine trough concentration was 29.7 ng/mL (95% CI: 23.8–37). No patient presented rilpivirine plasma concentrations under the proposed threshold. The mean rilpivirine concentration in CSF was 0.8 ng/mL (95% CI: 0.7–1.0), representing a CSF : plasma ratio of 1.4%, with concentrations above the EC90 in 85% (11/13) of patients. In SP, the mean rilpivirine concentration was 4.9 ng/mL (95% CI: 3.3–7.2), representing an SP : plasma ratio of 9.5%, with all concentrations above the EC90. Conclusions Switching from nevirapine- to rilpivirine-containing antiretroviral therapy was safe and well tolerated, with plasma rilpivirine concentrations above the protein binding-adjusted EC90 in all subjects. Rilpivirine concentrations were always above the EC50 in the CSF and the EC90 in SP. [ABSTRACT FROM PUBLISHER]

Objectives Raltegravir pharmacokinetics (PK) show high intra- and inter-patient variability and are also influenced by co-administered substances that alter the gastrointestinal tract environment, such as pH-altering or metal-containing agents. The aim of this investigation was to develop a population-based absorption, distribution, metabolism and excretion (ADME) model to investigate the effects of gastrointestinal pH and ingested magnesium on raltegravir PK. Methods In vitro data describing the disposition of raltegravir were obtained from literature sources or generated by standard methods. Raltegravir (400 mg single dose) PK were simulated in healthy volunteers (50 subjects per group, 20–50 years old, 0.5 proportion female subjects) over a 12 h period. Results Simulated raltegravir PK correlated well with data from clinical trials, with a mean deviation in Cmax, AUC0-12 and Ctrough of <20%. Solubility of raltegravir in the gastrointestinal tract was increased at higher luminal pH. Increased intestinal pH and transit time both correlated with higher raltegravir absorption (P < 0.001). Magnesium ingestion reduced raltegravir exposure in simulated subjects, with mean Ctrough reduced by 32% (P < 0.001). Conclusions The in vitro–in vivo extrapolation model developed in this study predicted raltegravir PK in virtual individuals with different gastrointestinal pH profiles. The main PK variables were predicted with good accuracy compared with reference data, and both luminal pH and magnesium were able to influence drug absorption. This modelling system provides a tool for investigating the absorption of other drugs, including HIV integrase inhibitors currently in development, which have also shown interactions with food and metal-containing products. [ABSTRACT FROM PUBLISHER]

Background Once-daily nucleoside-sparing combination antiretroviral therapy regimens are attractive options for the treatment of HIV infection. However, the pharmacokinetic profiles of such regimens are often not established. Methods HIV-infected subjects receiving 245/200 mg of tenofovir/emtricitabine plus 800/100 mg of darunavir/ritonavir once daily with plasma HIV RNA <50 copies/mL were eligible. On day 1 (period 1), 150 mg of maraviroc daily was added and on day 11 (period 2), tenofovir/emtricitabine discontinued. At steady-state (days 10 and 20), intensive pharmacokinetic sampling was undertaken. We assessed (i) the number of subjects with trough (Ctrough) and average (Cavg) maraviroc concentrations <25 and <75 ng/mL, respectively; (ii) geometric mean (GM) ratios for pharmacokinetic parameters for period 2 versus period 1; and (iii) factors associated with total maraviroc exposure. Results Eleven subjects completed the study procedures (mean age 49 years; range 35–59 years). In three subjects, maraviroc Ctrough and Cavg were <25 and <75 ng/mL, respectively (Cavg, 68 ng/mL and Ctrough, 14 and 21 ng/mL). Although not statistically significant, a trend was observed towards lower maraviroc, darunavir and ritonavir concentrations in period 2 versus period 1; total maraviroc exposure was 3579 ng· h/mL (95% CI: 2983–4294) and 2996 ng· h/mL (95% CI: 2374–3782) in periods 1 and 2, respectively, and the GM ratio was 0.84 (95% CI: 0.67–1.05). Only total ritonavir exposure was significantly associated with total maraviroc exposure (P = 0.049; 95% CI: 0.01–0.91). No clinical safety concerns were observed. Conclusions Within this novel nucleoside-sparing regimen, maraviroc exposure is dependent on ritonavir exposure, which was slightly reduced in the absence of tenofovir/emtricitabine. [ABSTRACT FROM PUBLISHER]

Objectives: The pharmacokinetic and pharmacodynamic effects of antiretroviral therapy may differ in older compared with younger subjects with HIV infection. We aimed to assess factors associated with plasma antiretroviral drug exposure, including age, within a large HIV-infected cohort undergoing therapeutic drug monitoring (TDM).Methods: Data from the Liverpool TDM Registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. All TDM of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was included and in order to account for different antiretroviral drugs the plasma concentrations were standardized by group measurements according to drug, dosing and timing of TDM. Regression modelling was used to evaluate associations of drug exposure with age and clinical parameters, including hepatic transaminase results and time to antiretroviral treatment modification.Results: Data from 3589 TDM samples were available from 2447 subjects. The greatest numbers of plasma concentrations were assessed for lopinavir (22.4%), efavirenz (18.5%), atazanavir (17.0%) and saquinavir (11.6%). As age increased, median standardized NNRTI concentrations remained constant, whereas PI concentrations increased (correlation coefficient 0.04, P = 0.033). In a regression analysis stratified by antiretroviral drug class, standardized plasma concentrations were significantly associated with age for PIs (0.05 increase in standard deviation of drug concentration with each 10 year increase in age, P = 0.044), but not for NNRTIs or other clinical parameters, including hepatic transaminase results or time to antiretroviral treatment modification.Conclusions: With increasing age, statistically significant rises in plasma PI exposure, but not NNRTI exposure, were observed. The clinical relevance of this observation merits further investigation. [ABSTRACT FROM AUTHOR]

Objectives Co-administration of artemether/lumefantrine with antiretroviral therapy has potential for pharmacokinetic drug interactions. We investigated drug–drug interactions between artemether/lumefantrine and efavirenz or nevirapine. Methods We performed a cross-over study in which HIV-infected adults received standard six-dose artemether/lumefantrine 80/480 mg before and at efavirenz or nevirapine steady state. Artemether, dihydroartemisinin, lumefantrine, efavirenz and nevirapine plasma concentrations were measured and compared. Results Efavirenz significantly reduced artemether maximum concentration (Cmax) and plasma AUC (median 29 versus 12 ng/mL, P < 0.01, and 119 versus 25 ng · h/mL, P < 0.01), dihydroartemisinin Cmax and AUC (median 120 versus 26 ng/mL, P < 0.01, and 341 versus 84 ng · h/mL, P < 0.01), and lumefantrine Cmax and AUC (median 8737 versus 6331 ng/mL, P = 0.03, and 280 370 versus 124 381 ng · h/mL, P < 0.01). Nevirapine significantly reduced artemether Cmax and AUC (median 28 versus 11 ng/mL, P < 0.01, and 123 versus 34 ng · h/mL, P < 0.01) and dihydroartemisinin Cmax and AUC (median 107 versus 59 ng/mL, P < 0.01, and 364 versus 228 ng · h/mL, P < 0.01). Lumefantrine Cmax and AUC were non-significantly reduced by nevirapine. Artemether/lumefantrine reduced nevirapine Cmax and AUC (median 8620 versus 4958 ng/mL, P < 0.01, and 66 329 versus 35 728 ng · h/mL, P < 0.01), but did not affect efavirenz exposure. Conclusions Co-administration of artemether/lumefantrine with efavirenz or nevirapine resulted in a reduction in artemether, dihydroartemisinin, lumefantrine and nevirapine exposure. These drug interactions may increase the risk of malaria treatment failure and development of resistance to artemether/lumefantrine and nevirapine. Clinical data from population pharmacokinetic and pharmacodynamic trials evaluating the impact of these drug interactions are urgently needed. [ABSTRACT FROM PUBLISHER]

Background Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir. Methods A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured. Results Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (Cmax) and area under the concentration–time curve (AUC) [median (range): 112 (20–362) versus 56 (17–236) ng/mL, P = 0.03; and 264 (92–1129) versus 151 (38–606) ng · h/mL, P < 0.01]. Dihydroartemisinin Cmax and AUC were not affected [66 (10–111) versus 73 (31–224) ng/mL, P = 0.55; and 213 (68–343) versus 175 (118–262) ng · h/mL P = 0.27]. Lumefantrine Cmax and AUC increased during co-administration [2532 (1071–5957) versus 7097 (2396–9462) ng/mL, P < 0.01; and 41 119 (12 850–125 200) versus 199 678 (71 205–251 015) ng · h/mL, P < 0.01]. Conclusions Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated. [ABSTRACT FROM PUBLISHER]

Objectives We designed two different studies to evaluate two different combination antiretroviral therapy (cART) stopping strategies namely a ‘staggered stop’ approach (STOP 1 study) and a ‘protected stop’ approach (STOP 2 study) to find the best ‘universal stop’ strategy. Patients and methods Patients who stopped cART for any reason were recruited. In STOP 1, 10 patients on efavirenz continued dual nucleos(t)ide reverse transcriptase inhibitors (NRTIs) for 1 week after discontinuing efavirenz. Efavirenz concentrations were measured weekly for up to 3 weeks. In STOP 2, 20 patients stopped their cART and replaced it with two tablets of lopinavir/ritonavir (Kaletra) (100/50 mg) twice daily for 4 weeks. Lopinavir, efavirenz, nevirapine and tenofovir concentrations were measured weekly for up to 4 weeks. Virological and resistance testing were performed. Results In STOP 1 five patients still had efavirenz present (median t1/2 = 148.4 h) 3 weeks after stopping. In STOP 2, 15/20 patients had a viral load (VL) of <40 copies/mL and 3/20 patients had a reduction in VL by 4 weeks. Six patients opted not to stop lopinavir/ritonavir and still had <40 copies/mL at week 8. Week 1–4 median trough lopinavir concentrations were well above the EC95. Six patients still had detectable concentrations of original cART persisting for >1 week after stopping. No patients developed new resistance mutations. Conclusions Plasma efavirenz concentrations can persist up to 3 weeks after patients stop efavirenz-containing regimens. This suggests a strategy of stopping efavirenz only 1 week before NRTIs may not be long enough for some individuals. The use of lopinavir/ritonavir monotherapy for a 4 week period may be an alternative pharmacologically and virologically effective universal stopping strategy which warrants further investigation. [ABSTRACT FROM PUBLISHER]

Background We conducted a pharmacokinetic and in vivo cerebral 1H magnetic resonance spectroscopy (1H-MRS) study to assess CSF exposure and cerebral metabolite ratios (CMRs) following maraviroc intensification. Methods HIV-infected neurologically asymptomatic adults receiving tenofovir, emtricitabine and lopinavir/ritonavir with plasma HIV RNA <50 copies/mL were eligible and received intensified therapy with 150 mg of maraviroc twice daily. 1H-MRS was performed in several cerebral locations, including the right basal ganglia (RBG), to assess CMRs, including N-acetyl aspartate/creatine (NAA/Cr), at baseline and after 14 days. Subsequently, on day 15, blood samples were obtained to determine plasma concentrations of maraviroc pre-dose (Ctrough) and then paired blood and CSF samples were collected at 4 or 6 h post-dose. Associations between maraviroc exposure, clinical parameters and changes to CMRs were evaluated. Trial registry: ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00982878). Results Twelve subjects (75% male) participated with a mean (SD) CD4+ cell count of 503 (199) cells/μL. Mean (SD) maraviroc plasma concentrations at pre-dose, 4 h post-dose and 6 h post-dose were 337 (74), 842 (174) and 485 (100) ng/mL and CSF concentrations at 4 h post-dose and 6 h post-dose were 7.5 (1.3) and 5.1 (1.2) ng/mL. The mean maraviroc CSF : plasma ratio (range) was 1.01% (0.57%–1.61%). An increase of 14.8% was observed for the RBG NAA/Cr ratio, which was significantly associated with higher maraviroc plasma Ctrough (P = 0.05, r = 0.61), but not CSF concentration (P = 0.16, r = 0.46). Conclusions After 14 days of maraviroc intensification, small increases in cerebral metabolite markers of neuronal integrity (NAA/Cr ratios) were observed and are associated with maraviroc plasma Ctrough. [ABSTRACT FROM PUBLISHER]

Objectives To compare the use of co-medication, the potential drug–drug interactions (PDDIs) and the effect on antiretroviral therapy (ART) tolerability and efficacy in HIV-infected individuals according to age, ≥50 years or <50 years. Methods All ART-treated participants were prospectively included once during a follow-up visit of the Swiss HIV Cohort Study. Information on any current medication was obtained by participant self-report and medical prescription history. The complete treatment was subsequently screened for PDDIs using a customized version of the Liverpool drug interaction database. Results Drug prescriptions were analysed for 1497 HIV-infected individuals: 477 age ≥50 and 1020 age <50. Older patients were more likely to receive one or more co-medications compared with younger patients (82% versus 61%; P < 0.001) and thus had more frequent PDDIs (51% versus 35%; P < 0.001). Furthermore, older patients tended to use a higher number of co-medications and certain therapeutic drug classes more often, such as cardiovascular drugs (53% versus 19%; P < 0.001), gastrointestinal medications (10% versus 6%; P = 0.004) and hormonal agents (6% versus 3%; P = 0.04). PDDIs with ART occurred mainly with cardiovascular drugs (27%), CNS agents (22%) and methadone (6%) in older patients and with CNS agents (27%), methadone (15%) and cardiovascular drugs (11%) in younger patients. The response to ART did not differ between the two groups. Conclusions The risk for PDDIs with ART increased in older patients who take more drugs than their younger HIV-infected counterparts. However, medication use in older and younger patients did not differ in terms of effect on antiretroviral tolerability and response. [ABSTRACT FROM PUBLISHER]

Background. Tenofovir (TFV) causes kidney tubular dysfunction (KTD) in some patients, but the mechanism is poorly understood. Genetic variants in TFV transporters are implicated; we explored whether ABCC10 transports TFV and whether ABCC10 single-nucleotide polymorphisms (SNPs) are associated with KTD.Methods. TFV accumulation was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4+ cells and monocyte-derived macrophages (MDMs). Substrate specificity was confirmed by cepharanthine (ABCC10 inhibitor) and small interfering RNA (siRNA) studies. Fourteen SNPs in ABCC10 were genotyped in human immunodeficiency virus–positive patients with KTD (n = 19) or without KTD (controls; n = 96). SNP and haplotype analysis was performed using Haploview.Results. TFV accumulation was significantly lower in HEK293-ABCC10 cell lines than in parental HEK293 cells (35% lower; P = .02); this was reversed by cepharanthine. siRNA knockdown of ABCC10 resulted in increased accumulation of TFV in CD4+ cells (18%; P = .04) and MDMs (25%; P = .04). Two ABCC10 SNPs (rs9349256: odds ratio [OR], 2.3; P = .02; rs2125739, OR, 2.0; P = .05) and their haplotype (OR, 2.1; P = .05) were significantly associated with KTD. rs9349256 was associated with urine phosphorus wasting (P = .02) and β2 microglobulinuria (P = .04).Conclusions. TFV is a substrate for ABCC10, and genetic variability within the ABCC10 gene may influence TFV renal tubular transport and contribute to the development of KTD. These results need to be replicated in other cohorts. [ABSTRACT FROM PUBLISHER]

Background Nevirapine is metabolized by CYP2B6 and polymorphisms within the CYP2B6 gene partly explain inter-patient variability in pharmacokinetics. The aim of this study was to model the complex relationship between nevirapine exposure, weight and genetics (based on combined analysis of CYP2B6 516G > T and 983T > C single nucleotide polymorphisms). Methods Non-linear mixed-effects modelling was used to estimate pharmacokinetic parameters from 275 patients. Simulations of the nevirapine concentration profile were performed with dosing regimens of 200 mg twice daily and 400 mg once daily for individuals with body weights of 50, 70 and 90 kg in combination with CYP2B6 genetic variation. Results A one-compartment model with first-order absorption best described the data. Population clearance was 3.5 L/h with inter-patient variability of 24.6%. 516T homozygosity and 983C heterozygosity were associated with 37% and 40% lower clearance, respectively. Body weight was the only significant demographic factor influencing clearance, which increased by 5% for every 10 kg increase. For individuals with higher body weight, once-daily nevirapine was associated with a greater risk of sub-therapeutic drug exposure than a twice-daily regimen. This risk was offset in individuals who were 516T homozygous or 983C heterozygous in which drug exposure was optimal for > 95% of patients with body weight of ≤70 kg. Conclusions The data suggest that a 400 mg once-daily dose could be implemented in accordance with CYP2B6 polymorphism and body weight. However, the use of nevirapine once daily (immediate release; off-label) in the absence of therapeutic drug monitoring is not recommended due to the risk of inadequate exposure to nevirapine in a high proportion of patients. There are different considerations for the extended-release formulation (nevirapine XR) that demonstrate minimal peak-to-trough fluctuations in plasma nevirapine levels. [ABSTRACT FROM PUBLISHER]

Objectives To assess the pharmacokinetics (PK) of raltegravir and ezetimibe when co-administered to healthy volunteers. Methods This was a prospective, open-label, crossover study, with subjects randomly assigned to group 1 (raltegravir 400 mg twice daily, raltegravir plus ezetimibe 10 mg once daily, wash-out period, ezetimibe) or group 2 (ezetimibe, raltegravir plus ezetimibe, wash-out period, raltegravir); all phases lasted for 10 days. Steady-state full PK sampling was performed at days 10, 20 and 40. Raltegravir and ezetimibe PK parameters were determined by non-compartmental methods and comparisons in the presence of the potentially interactive drug measured by geometric mean ratio (GMR) and 95% confidence intervals (CIs). Results Twenty subjects (10 females) completed the study. Raltegravir PK parameters did not change significantly in the presence of ezetimibe: GMRs (95% CI) were 1.16 (0.89–1.51) for AUC0–12, 1.13 (0.81–1.58) for maximum plasma concentration (Cmax) and 1.12 (0.72–1.74) for trough concentration (Ctrough). Ezetimibe AUC0–24 and Ctrough were lower in the presence of raltegravir [GMRs (95% CI) were 0.79 (0.68–0.91) for AUC0–24 and 0.78 (0.60–0.99) for Ctrough], while ezetimibe glucuronide Cmax was 40% higher (90% CI 1.17–1.66). There was marked inter-individual variability in the PK of the two drugs, especially during co-administration. Conclusions There were no significant changes in raltegravir PK parameters with or without ezetimibe. However, in the presence of raltegravir, ezetimibe AUC0–24 and Ctrough were significantly lower (>20%) and ezetimibe glucuronide Cmax was higher. Clinical data to assess the importance of the change in ezetimibe concentrations are warranted. [ABSTRACT FROM PUBLISHER]

Objectives: Data suggest that some licensed antiretroviral doses could be reduced. We assessed the safety, tolerability and pharmacokinetics of lopinavir/ritonavir at doses of 400/100, 200/150 and 200/50 mg twice daily in HIV-negative volunteers (http://clinicaltrials.gov/ct2/show/NCT00985543).Methods: Male and female volunteers were administered lopinavir/ritonavir at doses of 400/100 mg (two lopinavir/ritonavir Meltrex 200/50 mg tablets, Regimen 1), 200/150 mg (one Meltrex tablet, one 100 mg ritonavir capsule, Regimen 2) and 200/50 mg (one Meltrex tablet, Regimen 3). Each dose was given twice daily for 7 days sequentially, separated by a 7 day wash-out period. Lopinavir/ritonavir steady-state pharmacokinetics was assessed over 12 h at the end of each phase (days 7, 21 and 35). Pharmacokinetic parameters were compared using the 400/100 mg twice daily dose as reference, by determining geometric mean ratios (GMRs) and 90% confidence intervals.Results: Twenty-two subjects (eight females) completed the study. Lopinavir AUC(0-12) (ng h/mL), C(max) (ng/mL) and the minimum concentration (C(trough)) (ng/mL) for the 400/100, 200/150 and 200/50 mg twice daily doses, respectively, were as follows: 99,599, 73,603 and 45,146; 11,965, 8939 and 6404; and 5776, 4293 and 1749. Lopinavir pharmacokinetic parameters were significantly lower for Regimens 2 and 3: GMR (90% CI) AUC(0-12), 0.74 (0.65-0.84) and 0.45 (0.40-0.51); C(max), 0.75 (0.66-0.85) and 0.54 (0.40-0.60); and C(trough), 0.74 (0.62-0.89) and 0.30 (0.25-0.36), respectively. All subjects taking the 400/100 and 200/150 mg twice daily doses, and 19 (86%) subjects taking 200/50 mg twice daily had lopinavir concentrations above the suggested minimum effective concentration of 1000 ng/mL.Conclusions: These pharmacokinetic data show that therapeutic plasma concentrations of lopinavir can be achieved with 200/150 mg of lopinavir/ritonavir twice daily (one Meltrex tablet and one 100 mg ritonavir capsule twice daily). [ABSTRACT FROM AUTHOR]

Background Rifampicin lowers nevirapine plasma concentrations by inducing cytochrome P450. However, few data are available on this interaction during the lead-in period of nevirapine treatment. Methods Eighteen HIV-1/tuberculosis co-infected adults receiving rifampicin daily as part of anti-tuberculosis therapy were evenly randomized to nevirapine initiation by dose escalation (NVP200) or nevirapine initiation at 200 mg twice daily (NVP400). Subjects underwent 12 h intensive pharmacokinetic sampling on Days 7, 14 and 21 of nevirapine treatment. A minimum effective concentration (MEC) of 3000 ng/mL was used to interpret nevirapine concentrations 12 h after dosing (C12). Trial registration number: NCT00617643 (www.clinicaltrials.gov). Results Day 7 geometric mean nevirapine C12 [90% confidence interval (CI)] was 1504 (1127–2115) ng/mL and 3148 (2451–4687) ng/mL in the NVP200 and NVP400 arms, respectively (P < 0.01). Nevirapine C12 on Days 14 and 21 was similar. On Day 21, nevirapine concentration in 64% of patients was below the MEC. On Day 7, geometric mean area under the curve (AUC0–12) was lower in the NVP200 arm, 25 223 (90% CI, 21 978–29 695) ng·h/mL versus 43 195 (35 607–57 035) ng·h/mL in the NVP400 arm (P < 0.01). Similarly, on Day 14, nevirapine AUC0–12 was lower in the NVP200 arm 23 668 (18 253–32 218) ng·h/mL versus the NVP400 arm 44 918 (36 264–62 769) ng·h/mL (P = 0.03). Conclusions In co-treated patients, nevirapine concentrations were below the MEC during initiation with dose escalation. Nevirapine initiation at the maintenance dose of 200 mg twice daily is preferred. Sub-therapeutic nevirapine concentrations were common at Day 21 with either regimen. Evaluation of higher nevirapine maintenance doses may be considered. [ABSTRACT FROM PUBLISHER]

Recent advances in the development of agents that act specifically to inhibit hepatitis C virus (HCV) are set to fundamentally change the way that patients will be treated. New directly acting anti-HCV agents such as protease and polymerase inhibitors will initially be added to standard of care with pegylated interferon-α and ribavirin. However, future therapy is likely to constitute combinations of agents which act at distinct stages of viral replication and have differing resistance profiles. While directly acting anti-HCV agents will undoubtedly improve treatment outcomes, the introduction of combination therapy may not be without complications in some patient groups. HIV-positive patients who are receiving antiretrovirals (ARVs) are relatively highly represented among those with HCV infection, and are at high risk of drug–drug interactions (DDIs). As combination anti-HCV treatment gradually evolves to resemble anti-HIV therapy, it is essential to consider the increased potential for DDIs in patients receiving combination anti-HCV therapy, and particularly in HCV/HIV-co-infected individuals. Therapeutic drug monitoring is likely to play a role in the clinical management of such interactions. [ABSTRACT FROM PUBLISHER]

Background: The intracellular and plasma concentrations of HIV protease inhibitors (HPIs) vary widely in vivo. It is unclear whether there is a concentration-dependent effect of HPIs such that at increasing concentration they may either block their own efflux (leading to 'autoboosting') or influx (leading to saturability/decreased intracellular accumulation). Method: The effects of various concentrations (0-30 µM) of lopinavir, saquinavir, ritonavir and atazanavir on the accumulation of [14C]lopinavir, [³H]saquinavir, [³H]ritonavir and [³H]atazanavir, respectively, were investigated in CEMparental, CEMVBL [P-glycoprotein (ABCB1) overexpressing], CEME1000 (MRP1 overexpressing) and in peripheral blood mononuclear cells (PBMCs). We also investigated the effects of inhibitors of ABCB1/ABCG2 (tariquidar), ABCC (MK571) and ABCC1/2 (frusemide), singly and in combination with HPIs, on cellular accumulation. Results: In all the cell lines, with increasing concentration of lopinavir, saquinavir and ritonavir, there was a significant increase in the cellular accumulation of [14C]lopinavir, [³H]saquinavir and [³H]ritonavir. Tariquidar, MK571 and frusemide (alone and in combination with lopinavir, saquinavir and ritonavir) significantly increased the accumulation of [14C]lopinavir, [³H]saquinavir and [³H]ritonavir. Ritonavir (alone or in combination with tariquidar) decreased the intracellular accumulation of [³H]ritonavir in PBMCs. Atazanavir decreased the accumulation of [³H]atazanavir in a concentration-dependent manner in all of the cells tested. Conclusions: There are complex and variable drug-specific rather than class-specific effects of the HPIs on their own accumulation. [ABSTRACT FROM AUTHOR]

Background: The protease inhibitors lopinavir and atazanavir are both recommended for treatment of HIV-infected patients. Considerable inter-individual variability in plasma concentration has been observed for both drugs. The aim of this study was to evaluate which demographic factors and concomitant drugs are associated with lopinavir and atazanavir plasma concentration. [ABSTRACT FROM PUBLISHER]

Objectives: To determine the relationship between nutritional status and nevirapine exposure by comparing the pharmacokinetics of nevirapine in HIV-infected children of different ages with and without malnutrition receiving divided tablets of Triomune®30 (stavudine + lamivudine + nevirapine) in accordance with Malawi National Guidelines. [ABSTRACT FROM PUBLISHER]

Background: Interaction of antiretrovirals with drug transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), breast cancer resistance protein (BCRP) and solute carrier organic anion transporter (SLCO) may influence the emergence of viral mutants by altering intracellular drug concentrations. Here we characterize the effect of transporter expression in a variety of cell types such as control CEM, CEMVBL (P-gp-overexpressing), CEME1000 (MRP1-overexpressing), MT4, control MDCKII, MDCKIIMDR1 (P-gp-overexpressing) and peripheral blood mononuclear cells (PBMCs) on the uptake of [14C]efavirenz and [3H]nevirapine. We also investigated the lipophilicity of [14C]efavirenz and [3H]nevirapine. [ABSTRACT FROM PUBLISHER]

Background. Tenofovir is one of the most widely used antiretroviral drugs. Tenofovir undergoes renal clearance by a combination of glomerular filtration and active tubular secretion. Although rare, the mechanism by which tenofovir causes renal damage is not well characterized. We have explored the association between kidney tubular dysfunction (KTD) and polymorphisms in genes encoding drug transporters. Methods. All consecutive, human immunodeficiency virus (HIV)-infected patients receiving tenofovir-containing antiretroviral regimens who were seen at a single institution during the first trimester of 2008 were enrolled in the study. KTD was defined by the presence of at least 2 of the following abnormalities: nondiabetic glucosuria, urine phosphate wasting, hyperaminoaciduria, β2-microglobulinuria, and increased fractional excretion of uric acid. Twelve single-nucleotide polymorphisms in the ABCC2, ABCC4, SCL22A6, SLC22A11, and ABCB1 genes were analyzed using TaqMan 5′-nuclease assays. Results. A total of 115 HIV-infected patients were examined, of whom 19 (16.5%) had KTD. The percentage of patients with KTD was higher among those with genotype CC at position -24 of ABCC2 than among those with genotypes CT and TT (24% [16 of 68 patients] vs. 6% [3 of 47 patients]; Pp.020). In a multivariate analysis, older age (odds ratio [OR], 1.1; 95% confidence interval [CI], 1.0-1.2; Pp.024), lower body weight (OR, 0.9; 95% CI, 0.8-0.9; Pp.048), and genotype CC at ABCC2 position -24 (OR, 5; 95% CI, 1.2-21; Pp.027) were independently associated with KTD. Conclusions. Approximately 17% of HIV-infected patients treated with tenofovir had KTD. Homozygosity for the C allele at position -24 of the ABCC2 gene was strongly associated with KTD in this population. This polymorphism may help to identify patients at greater risk for developing tenofovir-associated tubulopathy, and close monitoring of renal function is warranted for these patients. [ABSTRACT FROM AUTHOR]

This study investigated pregnane X receptor polymorphisms in relation to unboosted atazanavir plasma concentrations in 2 cohorts of patients. The polymorphism 63396T→C predicted concentrations below the minimum effective concentration (150 ng/mL) with odds ratios of 18 (P=.008) and 5.13 (P=.02). Prospective studies determining potential clinical usefulness are now warranted. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate the frequency of CYP2B6 polymorphisms (according to ethnicity) and the influence of heterozygosity and homozygosity on plasma concentrations of efavirenz and nevirapine.Methods: Following written informed consent, 225 Caucasians and 146 Blacks were recruited from the German Competence Network for HIV/AIDS. Plasma concentrations of efavirenz and nevirapine were assessed by HPLC, and genotyping for 516G>T, 983T>C and 1459T>C polymorphisms in CYP2B6 was conducted by real-time PCR-based allelic discrimination.Results: The minor allele frequency for 516G>T, 983T>C and 1459T>C was 0.29, 0 and 0.08 in Caucasians and 0.34, 0.07 and 0.02 in Blacks, respectively. Two Black patients with the 983C allele receiving efavirenz were identified and both were withdrawn from therapy within 1 week of sampling due to toxicity. In multivariate analyses, efavirenz and nevirapine plasma concentrations were significantly associated with 983T>C (P < 0.0001 and P = 0.02, respectively), 516G>T (P < 0.0001 and P = 0.002, respectively) and time of drug analysis post-dose (P < 0.0001 for both). Body mass index was independently related to efavirenz (P = 0.04) but not nevirapine concentrations, and age was related to nevirapine (P = 0.05) but not efavirenz concentrations. Consistent with other studies, 1459C>T was not associated with plasma concentrations of either drug (P > 0.05 for both drugs).Conclusions: This is the first report that the 983T>C genotype (part of the CYP2B6*18 haplotype) impacts on nevirapine plasma concentrations and the first study to assess the impact of 983C homozygosity on efavirenz concentrations. These data have implications for administration of non-nucleoside reverse transcriptase inhibitors to Black patients. [ABSTRACT FROM AUTHOR]

Objectives: To examine cellular and plasma concentrations of atazanavir when given in combination with saquinavir/ritonavir in HIV+ patients. Methods: Twelve HIV+ patients were receiving saquinavir/atazanavir/ritonavir 1600/200/100 mg once daily and venous blood samples were taken to determine cellular and plasma concentrations of each protease inhibitor at 2, 6, 12 and 24 h. Peripheral blood mononuclear cells were separated by density gradient centrifugation. The ratio of the cellular AUC0-24/plasma AUC0-24 was calculated to determine cellular drug accumulation. Lymphocyte P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) expression was determined by flow cytometry. Nine of the patients had previously received a regimen of saquinavir/ritonavir 1600/100 mg; therefore the effect of atazanavir on the cellular and plasma pharmacokinetics of saquinavir and ritonavir was examined. Results: In vivo cellular and plasma determinations of saquinavir, atazanavir and ritonavir gave accumulation ratios of 4.9, 1.2 and 1.7, respectively. There was no relationship between saquinavir, atazanavir or ritonavir accumulation and P-gp, MRP1 or BCRP expression. When comparing pharmacokinetic values in the nine patients receiving saquinavir/ritonavir with and without atazanavir, the median cellular saquinavir AUC0-24 was significantly increased (34.9-117.2 mg.h/L) on addition of atazanavir (P=0.004). The C24 of saquinavir in plasma and cells was significantly higher with atazanavir (plasma C24 0.05 versus 0.14 mg/L with atazanavir; cellular C24 0.61 versus 2.03 mg/L with atazanavir, P=0.02). Conclusions: The mechanism of differential intracellular protease inhibitor accumulation is unclear. Co-administration of atazanavir caused an increase in both the plasma and cellular exposure (AUC0-24) and C24 of saquinavir but not ritonavir. [ABSTRACT FROM AUTHOR]

The present study evaluated the effect of cimetidine, a histamine H(2) receptor antagonist able to inhibit cytochrome P450 metabolism, on the steady-state pharmacokinetics of saquinavir soft gel. Twelve healthy volunteers (eight males and four females) participated in an open-label, double-phase pharmacokinetic study. Volunteers took saquinavir soft gel 1200 mg three times a day for 13 days and then saquinavir soft gel 1200 mg twice a day with cimetidine 400 mg twice a day from day 14 to 26. The pharmacokinetics of saquinavir on days 13 and 26 were compared. All 12 volunteers completed the study. The association of cimetidine with saquinavir soft gel 1200 mg twice a day resulted in a significant increase in saquinavir AUC(0-24) (120%; P = 0.023) and C(max) (179%; P = 0.019), whereas C(trough) did not differ significantly (32% increase; P = 0.272). Increased exposure to saquinavir was observed in healthy volunteers after co-administration with cimetidine. The most significant increase involved C(max). Further pharmacokinetic studies in HIV-infected subjects are warranted to confirm the boosting effect of cimetidine and to investigate any impact that the increase in saquinavir C(max) may have on intracellular accumulation of the drug. [ABSTRACT FROM AUTHOR]

Variable drug penetration of antiretroviral drugs into the genital tract may contribute to the differential evolution of HIV and the emergence of drug resistance. This, in turn, may have an impact on the sexual transmission of resistant HIV in patients treated with antiretroviral drugs. We have measured concentrations of the HIV-1 protease inhibitors indinavir, ritonavir and saquinavir in the blood plasma (BP) and seminal plasma (SP) of 23 HIV-1-positive men. Forty-five time-matched blood and semen samples were obtained. SP concentrations of indinavir exceeded the EC95 of indinavir, corrected for protein binding, of 42 ng/mL at all time intervals. In contrast, the median ritonavir and saquinavir SP concentrations were below the relevant EC95 at all times post drug ingestion. The median SP:BP concentration ratios for indinavir were 0.6, 0.8 and 1.4, respectively, at 0-2, 2-6 and 6-8 h post-drug ingestion. In contrast, the median SP:BP concentration ratios at 0-3, 3-9 and 9-12 h post-drug ingestion were <0.02, <0.04 and <0.04, respectively, for both ritonavir and saquinavir. These differences justify further study of HIV-1 evolution and development of resistance in the genital tract of men taking these anti-HIV drugs. [ABSTRACT FROM AUTHOR]

Scale-up of HIV treatment services may have contributed to an increase in functional health facilities available in resource-limited settings and an increase in patient use of facilities and retention in care. As more patients are reached with medicines, monitoring patient safety is increasingly important. Limited data from resource-limited settings suggest that medication error and antiretroviral drug–drug interactions may pose a significant risk to patient safety. Commonly cited causes of medication error in the developed world include the speed and complexity of the medication use cycle combined with inadequate systems and processes. In resource-limited settings, specific factors may contribute, such as inadequate human resources and high disease burden. Management of drug–drug interactions may be complicated by limited access to alternative medicines or laboratory monitoring. Improving patient safety by addressing the issue of antiretroviral drug–drug interactions has the potential not just to improve healthcare for individuals, but also to strengthen health systems and improve vital communication among healthcare providers and with regulatory agencies. [ABSTRACT FROM PUBLISHER]

We assessed the risk of clinically significant drug interactions in patients receiving antiretrovirals, and their recognition by physicians. Clinically significant drug interactions were recorded in 27% of 159 patients, with 15% of interactions potentially lowering antiretroviral concentrations. Risk of clinically significant drug interactions was significantly related to receipt of protease inhibitors. Only 36% of clinically significant drug interactions were correctly identified by physicians. [ABSTRACT FROM PUBLISHER]