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Background: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin., Methods: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with human immunodeficiency virus (HIV) on atazanavir/ritonavir-based antiretroviral therapy (ART) in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg twice a day (BID) with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data were interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L., Results: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, whereas 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported a serious adverse event (SAE) or experienced rebound viraemia., Conclusions: Twice daily atazanavir/ritonavir during rifampicin co-administration was well tolerated and achieved plasma concentrations above the target., Clinical Trials Registration: NCT04121195. Registered on 09 October 2019, https://clinicaltrials.gov/ct2/show/NCT04121195., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The coformulated lopinavir/ritonavir significantly reduces quinine concentration in healthy volunteers due to potential drug-drug interactions (DDIs). However, DDI information in malaria and HIV coinfected patients are lacking. The objective of the study was to apply physiologically-based pharmacokinetic (PBPK) modeling to predict optimal dosage regimens of quinine when coadministered with lopinavir/ritonavir in malaria and HIV coinfected patients with different conditions. The developed model was validated against literature. Model verification was evaluated using the accepted method. The verified PBPK models successfully predicted unbound quinine disposition when coadministered with lopinavir/ritonavir in coinfected patients with different conditions. Suitable dose adjustments to counteract with the DDIs have identified in patients with various situations (i.e., a 7-day course at 1,800 mg t.i.d. in patients with malaria with HIV infection, 648 mg b.i.d. in chronic renal failure, 648 mg t.i.d. in hepatic insufficiency except for severe hepatic insufficiency (324 mg b.i.d.), and 648 mg t.i.d. in CYP3A4 polymorphism)., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CL int.app. ) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL int.app. in a concentration-dependent manner. Linear regression analysis showed that log 10 RTV and log 10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL int.app. , where β was equal to -234 (95% confidence interval [CI] = -275 to -193; P < 0.0001) and -73 (95% CI = -89 to -57; P < 0.0001), respectively. RTV was more effective in lowering 10 μM RIF-induced elevations in DRV CL int.app. (half-maximal [50%] inhibitory concentration [IC 50 ] = 0.025 μM) than COBI (IC 50 = 0.223 μM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL int.app. , with RTV being more potent than COBI. These data provide the first in vitro experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and M. tuberculosis ., (Copyright © 2017 American Society for Microbiology.)

Considerable scope exists to vary the physical and chemical properties of nanoparticles, with subsequent impact on biological interactions; however, no accelerated process to access large nanoparticle material space is currently available, hampering the development of new nanomedicines. In particular, no clinically available nanotherapies exist for HIV populations and conventional paediatric HIV medicines are poorly available; one current paediatric formulation utilizes high ethanol concentrations to solubilize lopinavir, a poorly soluble antiretroviral. Here we apply accelerated nanomedicine discovery to generate a potential aqueous paediatric HIV nanotherapy, with clinical translation and regulatory approval for human evaluation. Our rapid small-scale screening approach yields large libraries of solid drug nanoparticles (160 individual components) targeting oral dose. Screening uses 1 mg of drug compound per library member and iterative pharmacological and chemical evaluation establishes potential candidates for progression through to clinical manufacture. The wide applicability of our strategy has implications for multiple therapy development programmes., Competing Interests: M.G., T. O. M., P.M., D.S., S.P.R. and A.O. have filed patents relating to the LPV SDNs and LPV/RTV combination SDNs described herein. The remaining authors declare no competing financial interests.

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., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Ritonavir is a protease inhibitor utilized primarily as a pharmaco-enhancer with concomitantly administered antiviral drugs including other protease inhibitors. However, poor tolerance, serious side effects, and toxicities associated with drug-drug interactions are common during exposure to ritonavir. The aim of this work was to investigate the impact of nanoformulation on ritonavir pharmacological properties. Emulsion-templated freeze-drying techniques were used to generate ritonavir (10 wt %) solid drug nanoparticle formulations. A total of 68 ritonavir formulations containing various mixtures of excipients were assessed for inhibition of CYP3A4 in baculosomes and primary human hepatocytes. Accumulation and cytotoxicity were assessed in HepG2 (hepatocytes), Caco-2 (intestinal), THP-1 (monocytes), A-THP-1 (macrophage), and CEM (lymphocytes). Transcellular permeation across Caco-2 cells was also assessed. From 68 solid drug nanoparticle formulations tested, 50 (73.5%) for baculosome and 44 (64.7%) for human primary hepatocytes exhibited enhanced CYP3A4 inhibition relative to an aqueous ritonavir solution. Sixty-one (89.7%) and 49 (72%) solid drug nanoformulations had higher apical to basal permeation across Caco-2 cells than aqueous solution of ritonavir after 60 and 120 min, respectively. No significant difference in cellular accumulation was observed for any solid drug nanoparticle for any cell type compared to aqueous ritonavir. However, incubation with the vast majority of solid drug nanoparticle formulations resulted in lower cytotoxicity of ritonavir than detected with an aqueous solution. These data provide in vitro proof of concept for improved inhibition of CYP3A4 by ritonavir through formation of solid drug nanoparticles. Nanodispersions also showed enhanced permeability across Caco-2 cells lower cytotoxicity across hepatic, intestinal, and immune cell types compared to an aqueous solution of ritonavir.

Objectives: Ritonavir, used at low doses as a boosting agent of other protease inhibitors (PIs), is known to be associated with metabolic complications and gastrointestinal disturbances. The rate of accumulation of ritonavir within cells is still debated due to scarce data and methodological limitations. Therefore, our aim was to evaluate intracellular ritonavir penetration when used with different boosted PIs in the clinical setting., Methods: Patients administered with atazanavir/ritonavir (300/100 mg, once daily), darunavir/ritonavir [600/100 mg, twice daily (darunavir-600) and 800/100 mg, once daily (darunavir-800)], lopinavir/ritonavir (400/100 mg, twice daily) and tipranavir/ritonavir (500/200 mg, twice daily) were considered. Blood sampling at the end of the dosing interval (Ctrough) was performed. Peripheral blood mononuclear cell (PBMC)-associated and plasma ritonavir and PI concentrations were measured by validated HPLC methods. PBMC count and individual mean cell volume (MCV) were measured using a Coulter Counter instrument., Results: One hundred patients were enrolled. Frequencies of ritonavir-boosted PIs were atazanavir, 37%; darunavir-600, 23%; lopinavir, 19%; tipranavir, 13%; and darunavir-800, 8%. The median intracellular and plasma concentrations of ritonavir were 1279 ng/mL (IQR 727-2087) and 170 ng/mL (IQR 82-384), respectively, accounting for a cellular accumulation ratio of 7.69 (5.7-10.9). Significant differences in ritonavir intracellular concentrations emerged among different PIs (P<0.001): specifically between darunavir-600 and atazanavir (P<0.001), between darunavir-600 and tipranavir (P=0.009), between atazanavir and lopinavir (P<0.001) and between lopinavir and tipranavir (P=0.027)., Conclusions: Our study showed a higher rate of ritonavir intracellular accumulation than previously reported, possibly due to the more accurate calculation of intracellular concentrations by MCV. The ratio varied according to concomitantly administered PIs, suggesting their influence on the rate of ritonavir intracellular penetration.

Objectives: To compare cerebrospinal fluid (CSF) darunavir and ritonavir concentrations in patients receiving darunavir/ritonavir 800/100 mg once daily or 600/100 mg twice daily. To determine the influence of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters (ABCB1 3435 C>T, ABCB1 1236 C>T, ABCB1 2677 G>T, SLCO1A2 38 A>G, SLCO1A2 516 A>C, ABCC2 -24 G>A) on darunavir and ritonavir penetration into CSF., Design: Comparative pharmacokinetics study in patients., Methods: Plasma and CSF darunavir and ritonavir concentrations (2-26 h after drug intake) were determined by a validated HPLC coupled with mass spectrometry method in adults on darunavir-based combination antiretroviral therapy undergoing a lumbar puncture., Results: HIV-infected patients on once-daily darunavir/ritonavir had significantly lower CSF darunavir trough concentrations and CSF-to-plasma ratios than patients on darunavir/ritonavir twice-daily (10.7 versus 38.2 ng/ml and 0.32 versus 0.90%; P < 0.05). No significant effect of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters was noted apart from slightly higher CSF darunavir penetration in patients carrying OATP1A2 uncommon variants., Conclusions: This is the first study to compare darunavir CSF concentrations in patients taking the once-daily or the twice-daily dosage: our data show that darunavir and ritonavir dosing significantly affects not only CSF concentrations but also the extent of drug penetration into the CSF. Furthermore a minority of patients in the once-daily arm presented very low CSF concentration of potential concern for HIV control in the central nervous system. The relative importance of pharmacogenetics in influencing CSF darunavir pharmacokinetics deserves further clinical investigation.

Objectives: To describe the pharmacokinetics of maraviroc when dosed at 150 or 300 mg once daily with 800/100 mg of darunavir/ritonavir., Methods: A retrospective case-note review of HIV-infected adults taking maraviroc was conducted. Patients on a maraviroc-based regimen for a minimum of 5 weeks were grouped as receiving: (i) 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine; (ii) 300 mg of maraviroc once daily with 800/100 mg of darunavir/ritonavir once daily; and (iii) 150 mg of maraviroc once daily with 800/100 mg of darunavir/ritonavir once daily. C(trough) and C(peak) data were collected at 2, 12 or 24 h post-dose., Results: Sixty-six patients were included, providing 115 samples. The median (IQR) C(peak) was 378 (350-640) ng/mL for 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine (n=9), 728 (378-935) ng/mL for 300 mg of maraviroc once daily with darunavir/ritonavir (n=29) and 364 (104-624) ng/mL for 150 mg of maraviroc once daily with darunavir/ritonavir (n=2; P=0.24). The median (IQR) C(trough) was 46 (33-61) ng/mL for 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine (n=12), 70 (49-97) ng/mL for 300 mg of maraviroc once daily with darunavir/ritonavir (n=34) and 43 (35-55) ng/mL for 150 mg of maraviroc once daily with darunavir/ritonavir (n=17; P=0.001). The maraviroc C(trough) in black patients (n=34) was 61 (45-110) ng/mL and in white patients (n=29) it was 49 (42-70) ng/mL (P=0.04). The C(peak) in black patients (n=20) was 800 (397-1060) ng/mL versus 387 (336-723) ng/mL in white patients (n=20; P=0.02)., Conclusions: Once daily coadministration of 300 mg of maraviroc with 800/100 mg of darunavir/ritonavir was well tolerated and had favourable pharmacokinetics when compared with 300 mg of maraviroc twice daily with 245 mg of tenofovir/200 mg of emtricitabine. A 24% higher C(trough) and 107% higher C(peak) was seen in black patients compared with white patients.

Fifty-five patients placed on tipranavir/ritonavir 500/200 mg twice a day (27 with enfuvirtide and 28 without) underwent tipranavir and ritonavir plasma concentration measurements by high-pressure liquid chromatography. Markedly higher tipranavir and ritonavir trough concentrations were observed in enfuvirtide recipients. The modelling of sparse plasma samples using a first order absorption and elimination monocompartmental model without time lag predicted higher tipranavir elimination half-life and volume of distribution in enfuvirtide takers. This unexpected drug-drug interaction warrants further investigation.

Background: Pharmacokinetic data are lacking for progestin-releasing subdermal contraceptive implants when used with either rilpivirine- or darunavir/ritonavir-based ART.Objectives: To characterize the pharmacokinetics of etonogestrel or levonorgestrel implants when administered with these ART regimens over 48 weeks.Patients and Methods: Two separate, parallel, three-group, non-randomized, pharmacokinetic studies evaluated either etonogestrel or levonorgestrel in women receiving rilpivirine- or darunavir-based ART compared with women without HIV (control group). Participants on ART were switched to rilpivirine-based ART with a run-in period of 6 weeks or darunavir-based ART with a run-in of 2 weeks prior to implant insertion. Plasma was collected on Day 0, and 1, 4, 12, 24, 36 and 48 weeks post-insertion. Plasma progestin concentrations were compared between ART and control groups by geometric mean ratio (GMR) and 90% CI.Results: At the primary endpoint of Week 24, progestin concentrations were similar between the rilpivirine and control groups [etonogestrel: 1.18 (0.99-1.37); levonorgestrel: 1.16 (0.97-1.33)]. At Week 24, progestin exposure was higher in the darunavir groups compared with the control group [etonogestrel: 2.56 (1.69-3.28); levonorgestrel: 1.89 (1.38-2.29)]. Results remained consistent through to Week 48. No differences in etonogestrel-related adverse events were observed, but both ART groups experienced more menstrual abnormalities versus the control group with levonorgestrel.Conclusions: Etonogestrel and levonorgestrel concentrations were not altered by rilpivirine-based ART. Although progestin concentrations were higher in the ART groups containing ritonavir-boosted darunavir, no implant-related serious adverse events were observed. Both progestin-releasing implants are an appropriate contraceptive option with either rilpivirine- or darunavir/ritonavir-based ART. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to simulate the drug–drug interaction (DDI) between ritonavir-boosted atazanavir (ATV/r) and rifampicin (RIF) using physiologically based pharmacokinetic (PBPK) modelling, and to predict suitable dose adjustments for ATV/r for the treatment of people living with HIV (PLWH) co-infected with tuberculosis. Methods: A whole-body DDI PBPK model was designed using Simbiology 9.6.0 (MATLAB R2019a) and verified against reported clinical data for all drugs administered alone and concomitantly. The model contained the induction mechanisms of RIF and ritonavir (RTV), the inhibition effect of RTV for the enzymes involved in the DDI, and the induction and inhibition mechanisms of RIF and RTV on the uptake and efflux hepatic transporters. The model was considered verified if the observed versus predicted pharmacokinetic values were within twofold. Alternative ATV/r dosing regimens were simulated to achieve the trough concentration (Ctrough) clinical cut-off of 150 ng/mL. Results: The PBPK model was successfully verified according to the criteria. Simulation of different dose adjustments predicted that a change in regimen to twice-daily ATV/r (300/100 or 300/200 mg) may alleviate the induction effect of RIF on ATV Ctrough, with > 95% of individuals predicted to achieve Ctrough above the clinical cut-off. Conclusions: The developed PBPK model characterized the induction-mediated DDI between RIF and ATV/r, accurately predicting the reduction of ATV plasma concentrations in line with observed clinical data. A change in the ATV/r dosing regimen from once-daily to twice-daily was predicted to mitigate the effect of the DDI on the Ctrough of ATV, maintaining plasma concentration levels above the therapeutic threshold for most patients. [ABSTRACT FROM AUTHOR]

Introduction: In December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing. Methods: COVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website (www.covid19-druginteractions.org), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases. Findings: Remdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities. Conclusion: Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment. [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]

The images or other third-party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Correction to: Predicting Drug-Drug Interactions between Rifampicin and Ritonavir-Boosted Atazanavir Using PBPK Modelling If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. [Extracted from the article]

Introduction Treatment of HIV/TB co-infection is challenging due to high drug-drug interaction potential between antiretrovirals and rifamycins, such as rifampicin (RIF). The PK interaction between darunavir/ritonavir (DRV/RTV) and RIF has not been studied. Utilizing other protease inhibitor data, population PK modelling and simulation was applied to assess the impact of RIF on DRV/RTV PK and generate alternative dosing strategies to aid future clinical trial design. Materials and Methods A previously developed model describing DRV/RTV PK including data from three studies in HIV patients was used [n=51, 7 female, DRV/RTV 800/100 mg (n=32) or 900/100 mg once daily ( qd; n=19) []. The PK interaction between DRV/RTV and RIF was assumed to mimic that observed in HIV-infected, TB negative patients receiving lopinavir (LPV)/RTV (n=21) []. Simulations of DRV/RTV 800/100 mg qd (n=1000) were performed (-RIF). The model was adapted to increase the typical value of apparent oral clearance (CL/F) by 71% and 36% and decrease relative bioavailability (F) by 20% and 45% for DRV and RTV, respectively []; 1000 simulations were generated (+RIF). Dose adjustments of DRV/RTV 1200/200 mg qd, 800/100 mg and 1200/150 mg twice daily ( bid) were simulated to overcome the interaction. DRV trough (Ctrough) for each dosing scenario was compared to the reference (-RIF) by GMR (90% CI). Results DRV and RTV were described by a 1 and 2-compartment model, respectively. A maximum effect model, with RTV inhibiting DRV CL/F, best described the relationship between the drugs. Compared to the reference (-RIF), simulated DRV Ctrough was 70%, 46% and 20% lower for 800/100 mg qd, 1200/200 mg qd and 800/100 mg bid all +RIF, respectively. Ctrough was 38% higher with 1200/150 mg bid +RIF (Table 1). Conclusions Modelling and simulation was used to investigate the theoretical impact of RIF on DRV/RTV PK. Based on simulations, 800/100 mg and 1200/150 mg both bid could largely overcome the impact of the interaction. However, the risk of increased RTV-related side effects and higher pill burden should be considered. In vitro work is ongoing to develop a physiologically based model characterizing the interaction and informing simulations. [ABSTRACT FROM AUTHOR]