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Drug-drug interaction (DDI) may result in clinical toxicity or treatment failure of antiretroviral therapy (ARV) or comedications. Despite the high number of possible drug combinations, only a limited number of clinical DDI studies are conducted. Computational prediction of DDIs could provide key evidence for the rational management of complex therapies. Our study aimed to assess the potential of deep learning approaches to predict DDIs of clinical relevance between ARVs and comedications. DDI severity grading between 30,142 drug pairs was extracted from the Liverpool HIV Drug Interaction database. Two feature construction techniques were employed: 1) drug similarity profiles by comparing Morgan fingerprints, and 2) embeddings from SMILES of each drug via ChemBERTa, a transformer-based model. We developed DeepARV-Sim and DeepARV-ChemBERTa to predict four categories of DDI: i) Red: drugs should not be co-administered, ii) Amber: interaction of potential clinical relevance manageable by monitoring/dose adjustment, iii) Yellow: interaction of weak relevance and iv) Green: no expected interaction. The imbalance in the distribution of DDI severity grades was addressed by undersampling and applying ensemble learning. DeepARV-Sim and DeepARV-ChemBERTa predicted clinically relevant DDI between ARVs and comedications with a weighted mean balanced accuracy of 0.729 ± 0.012 and 0.776 ± 0.011, respectively. DeepARV-Sim and DeepARV-ChemBERTa have the potential to leverage molecular structures associated with DDI risks and reduce DDI class imbalance, effectively increasing the predictive ability on clinically relevant DDIs. This approach could be developed for identifying high-risk pairing of drugs, enhancing the screening process, and targeting DDIs to study in clinical drug development., (© 2024. The Author(s).)

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 (C trough ) 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 C trough , with > 95% of individuals predicted to achieve C trough 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 C trough of ATV, maintaining plasma concentration levels above the therapeutic threshold for most patients., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A significant number of new chemical entities in the drug development pipeline are poorly soluble, therefore routes that facilitate effective administration is of considerable value. Lipid nanoparticles have proved an attractive approach for drug delivery; however, challenges that include optimising drug loading and understanding the impact of drug physiochemical parameters on nanoparticle properties have limited progression. In this work, we investigate the effect of modifying the log  P of a model drug on the formation and stability of lipid-based nanoparticles. A range of model drug analogues with systematically varying alkyl chains were produced using a lamivudine (nucleoside analog reverse transcriptase inhibitor) scaffold and processed into lipid nanoparticles by nanoprecipitation. Characterisation included evaluation of particle diameter, size distribution, drug loading and nanoformulation stability. A distinct correlation with the LaMer model of nucleation was observed and log  P appeared to strongly influence rates of nucleation. Model drugs with high log  P were uniform in particle size and distribution and offered enhanced stability. In addition, various model drug/lipid blends were produced and their physical properties were investigated using dynamic light scattering (DLS) and differential scanning calorimetry (DSC). Complex mixtures of lipids were shown to influence formulation crystallinity and strategies to form uniform and stable lipid based nanoparticles of high drug loading- through manipulation of log  P are discussed.

Long-acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long-acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early- and late-stage clinical trials. Strategies to manage toxicity and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations. Long-acting injectable nanoformulations of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine were safe, well tolerated and efficacious in large randomised phase 3 studies. Regulatory approval for this two-drug combination for HIV maintenance therapy was granted in Canada in 2020 and is expected in the USA during 2021. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (islatravir) is a novel nucleoside reverse transcriptase inhibitor in clinical development as a long-acting oral drug and as a long-acting subcutaneous polymer implant. GS-6207 is a novel HIV capsid inhibitor that is injected subcutaneously every 3 months. Broadly-neutralising monoclonal antibodies have potent antiviral activity in early human trials, however there is substantial baseline resistance and rapid development of resistance to these antibodies if used as monotherapy. Limitations of these antiretroviral approaches include management of toxicities and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. These approaches appear to be especially attractive for patients complaining of pill fatigue and for those experiencing HIV-associated stigma. As these formulations are shown to be safe, well tolerated and economical, they are likely to gain broader appeal., (Copyright © 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/10 6 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/10 6 cells and 0.9 and 1.1 fmol/10 6 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications., (Copyright © 2020 American Society for Microbiology.)

Background: We previously demonstrated that etonogestrel concentrations were 82% lower in women using etonogestrel contraceptive implants plus efavirenz-based ART compared with women not receiving ART., Objectives: To investigate the genetic contribution to this previously observed drug-drug interaction through studying SNPs in genes known to be involved in efavirenz, nevirapine or etonogestrel metabolism in the same group of women., Patients and Methods: Here, we present a secondary analysis evaluating SNPs involved in efavirenz, nevirapine and etonogestrel metabolism and associated etonogestrel pharmacokinetics among 57 women, 19 not receiving ART (control group), 19 receiving efavirenz- (600 mg daily) based ART and 19 receiving nevirapine- (200 mg twice daily) based ART. Associations between patient genotype and etonogestrel pharmacokinetic parameters were determined through univariate and multivariate linear regression. This study was registered at clinicaltrials.gov (NCT02082652)., Results: Within the control group, CYP2B6 983 T>C was associated with 27% higher etonogestrel Cmax and 28% higher AUC0-24weeks. In the efavirenz group CYP2B6 516 G>T was associated with 43% lower etonogestrel Cmin and 34% lower AUC0-24weeks. For participants receiving nevirapine, NR1I2 63396 C>T was associated with 39% lower etonogestrel Cmin and 37% lower AUC0-24weeks., Conclusions: This study demonstrates the influence of pharmacogenetics on the extent of drug-drug interactions between etonogestrel and efavirenz- or nevirapine-based ART. Efavirenz plus the etonogestrel contraceptive implant results in a detrimental drug-drug interaction irrespective of patient genetics, which is worsened in women possessing variant alleles for these CYP2B6 SNPs., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Objectives: Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18 years) using physiologically-based pharmacokinetic modelling., Methods: Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations., Results: Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg., Conclusions: The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.

Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration ( C max ; 335 ng/ml), time to C max ( T max ; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC 0-24 ; 3,045 ng · h/ml), and concentration at 24 h ( C 24 ; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated C max (238 ng/ml), T max (3 h), AUC 0-24 (3,036 ng · h/ml), and C 24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies., (Copyright © 2017 American Society for Microbiology.)

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., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight -1 ) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median maximum concentrations of drug (C max ) were predicted to be 3,184 ng ml -1 (interquartile range [IQR], 2,219 to 4,851 ng ml -1 ), 49.9 ng ml -1 (IQR, 36.6 to 69.7 ng ml -1 ), and 50,343 ng ml -1 (IQR, 38,351 to 65,799 ng ml -1 ) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg -1 ), the median plasma and brain tissue concentrations in rats were 69.7 ng ml -1 (IQR, 44.9 to 130.6 ng ml -1 ) and 702.9 ng ml -1 (IQR, 475.5 to 1,018.0 ng ml -1 ), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution., (Copyright © 2016 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.

Strategies for reducing antiretroviral doses and drug costs can support global access, and numerous options are being investigated. Efavirenz pharmacokinetic simulation data generated with a bottom-up physiologically based model were successfully compared with data obtained from the ENCORE I clinical trial (efavirenz at 400 mg once per day versus 600 mg once per day). These findings represent a pivotal paradigm for the prediction of pharmacokinetics resulting from dose reductions. Validated computational models constitute a valuable resource for optimizing therapeutic options and predicting complex clinical scenarios., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

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., (© 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.)

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

Background and Objectives: Antiretrovirals are currently used for the treatment and prevention of HIV infection. However, poor adherence and low tolerability of some existing oral formulations can hinder their efficacy. Long-acting (LA) injectable nanoformulations could help address these complications by simplifying antiretroviral administration. The aim of this study is to inform the optimisation of intramuscular LA formulations for eight antiretrovirals through physiologically based pharmacokinetic (PBPK) modelling., Methods: A whole-body PBPK model was constructed using mathematical descriptions of molecular, physiological and anatomical processes defining pharmacokinetics. These models were validated against available clinical data and subsequently used to predict the pharmacokinetics of injectable LA formulations, Results: The predictions suggest that monthly intramuscular injections are possible for dolutegravir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir provided that technological challenges to control their release rate can be addressed., Conclusions: These data may help inform the target product profiles for LA antiretroviral reformulation strategies.

Objectives: Recent clinical data have suggested high raltegravir concentrations in gut tissue after oral administration, with implications for treatment and prevention. We have used in silico, in vitro, ex vivo and in vivo models to further investigate the accumulation of raltegravir in gut tissue., Methods: Affinity of raltegravir for gut tissue was assessed in silico (Poulin-Theil method), in vitro (Caco-2 accumulation) and ex vivo (rat intestine) and compared with the lipophilic drug lopinavir. Finally, raltegravir concentrations in plasma, gut contents, small intestine and large intestine were determined after oral dosing to Wistar rats 1 and 4 h post-dose. Samples were analysed using LC-MS/MS and scintillation counting., Results: Gut tissue accumulation of raltegravir was less than for lopinavir in silico, in vitro and ex vivo (P < 0.05). After oral administration to rats, raltegravir concentrations 4 h post-dose were lower in plasma (0.05 μM) compared with small intestine (0.47 μM, P = 0.06) and large intestine (1.36 μM, P < 0.05). However, raltegravir concentrations in the contents of both small intestine (4.0 μM) and large intestine (40.6 μM) were also high., Conclusions: In silico, in vitro and ex vivo data suggest low raltegravir accumulation in intestinal tissue. In contrast, in vivo animal data suggest raltegravir concentrates in intestinal tissue even when plasma concentrations are minimal. However, high raltegravir concentrations in gut contents are the likely driving factor behind this observation, rather than blood-to-tissue drug distribution. The methods described can be combined with clinical investigations to provide a complete strategy for selection of drugs with high gut accumulation., (© The Author 2014. 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.)

Rilpivirine is a nonnucleoside reverse transcriptase inhibitor approved for treatment of HIV-1 infection in antiretroviral-naive adult patients. Potential interactions with drug transporters have not been fully investigated. Transport by and inhibition of drug transporters by rilpivirine were analyzed to further understand the mechanisms governing rilpivirine exposure and determine the potential for transporter-mediated drug-drug interactions. The ability of rilpivirine to inhibit or be transported by ABCB1 was determined using ABCB1-overexpressing CEMVBL100 cells and Caco-2 cell monolayers. The Xenopus laevis oocyte heterologous protein expression system was used to clarify if rilpivirine was either transported by or inhibited the function of influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A2, SLC22A6, and SLC22A8. The ability of rilpivirine to inhibit or be transported by SLC22A1 was determined using SLC22A1-expressing KCL22 cells. Rilpivirine showed higher accumulation in SLC22A1-overexpressing KCL22 cells than control cells (27% increase, P = 0.03) and inhibited the functionality of SLC22A1 and SLC22A2 transport with 50% inhibitory concentrations (IC50s) of 28.5 μM and 5.13 μM, respectively. Inhibition of ABCB1-mediated digoxin transport was determined for rilpivirine, which inhibited digoxin transport in the B-to-A direction with an IC50 of 4.48 μM. The maximum rilpivirine concentration in plasma in patients following a standard 25-mg dosing regimen is around 0.43 μM, lower than that necessary to substantially inhibit ABCB1, SLC22A1, or SLC22A2 in vitro. However, these data indicate that SLC22A1 may contribute to variability in rilpivirine exposure and that interactions of rilpivirine with substrates of SLC22A1, SLC22A2, or ABCB1 may be possible.

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 C(max), AUC(0-12) and C(trough) 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 C(trough) 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.

Objective: To explore the effect of demographics and single-nucleotide polymorphisms in cytochrome P450 (CYP) 2B6, 2A6, UDP-glucuronosyltransferase (UGT) 2B7, and the constitutive androstane receptor (CAR) genes on efavirenz pharmacokinetics in a Chilean cohort affected with human immunodeficiency virus., Methods: Timed plasma samples obtained throughout the dosing interval were analyzed for efavirenz concentrations with liquid chromatography/tandem mass spectrometry. DNA from whole-blood samples was used for genetic analysis. Data were analyzed using a Mann-Whitney statistical test; furthermore, a Pearson or Spearman correlation was used. A multivariate analysis was then conducted using multiple linear regression by best subset analysis., Results: Overall 219 patients were included, 208 patients had measurable efavirenz levels and available genetic samples. The overall median (interquartile range) of efavirenz concentration was 2.6 (2.1-3.7) mcg/mL. In multivariate regression analysis, CYP2B6 516G>T (P < 0.0001) and CAR rs2307424 C>T (P = 0.002) were significantly related to efavirenz plasma concentrations., Conclusion: This novel association between CAR rs2307424 and efavirenz plasma concentrations now requires validation in other cohorts.

Heterogeneity in response to HIV treatments has been attributed to several causes including variability in pharmacokinetic exposure. Nanomedicine applications have a variety of advantages compared with traditional formulations, such as the potential to increase bioavailability and specifically target the site of action. Our group is focusing on the development of nanoformulations using a closed-loop design process in which nanoparticle optimization (disposition, activity and safety) is a continuous process based on experimental pharmacological data from in vitro and in vivo models. Solid drug nanoparticles, polymer-based drug-delivery carriers as well as nanoemulsions are nanomedicine options with potential application to improve antiretroviral deployment.

What Is Already Known About This Subject: • Nevirapine pharmacokinetics are affected by several factors including CYP2B6 single nucleotide polymorphisms (SNPs). These genetic profiles are more common in African patients and they affect the drug clearance being associated with higher trough concentrations. Pharmacokinetic/pharmacogenetic (PK/PG) studies are difficult to perform in remote areas where refrigeration is not available, although dried plasma and dried blood methods have been validated., What This Study Adds: • Dried plasma spots are useful tools for studying nevirapine PK with a good association to plasma concentrations and they can be used in rural areas since a cold chain is not necessary. Dried blood spots can be used to store and analyze patients' DNA for PG polymorphisms. Nevirapine trough concentrations in Burundese patients, not studied so far, are above the target concentration (3000 ng ml(-1) ) in 84% of patients. CYP2B6 (both at position 516 and 983) but not ABCB1 (3435 and 1236) SNPs as well as age correlate with higher nevirapine exposure., Aims: The pharmacokinetics (PK) and pharmacogenetics (PG) of nevirapine have been studied in rich and limited-resource countries. CYP2B6 single nucleotide polymorphisms (SNPs) have been associated with decreased drug clearance. We evaluated the PG determinants of nevirapine trough concentrations in a rural cohort in Burundi using easy to store and transport dried sample spot devices., Methods: A cross-sectional analysis in HIV-positive nevirapine-treated patients in Kiremba, north of Burundi, was performed in 2009. After blood withdrawal whole blood was stored on dried blood spots and plasma (after centrifugation) was placed on dried plasma spot devices and stored at room temperature. Nevirapine plasma and dried sample spot concentrations were compared to test the clinical usefulness of this method. SNPs in CYP2B6 and ABCB1 (using a real time PCR technique) were analyzed and associated with nevirapine plasma trough concentrations., Results: Nevirapine concentrations measured on dried plasma spot devices were highly related to plasma concentrations in 60 patients, although a negative bias was observed (-18%). Nevirapine trough concentrations were above the target concentration (3000 ng ml(-1) ) in 84% of patients and they were associated with CYP2B6 SNPs (both at position 516 and 983). No effect of ABCB1 SNPs was noted., Conclusions: Dried plasma spot devices are accurate tools for measuring nevirapine concentrations in rural settings where refrigeration is not available, despite a moderate underestimation bias. They allowed the evaluation of nevirapine concentrations in a cohort of HIV-infected people in rural Burundi, confirming very good exposure and correlation with PG polymorphisms in the CYP2B6 encoding gene., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

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.

Objectives: Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy., Methods: Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation., Results: Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months., Conclusions: These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations.

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.

A sensitive and accurate high performance liquid chromatography-mass spectrometric (HPLC-MS) method for the intracellular determination of 14 antiretroviral drugs in peripheral blood mononuclear cells (PBMCs) for HIV+ patients was validated. PBMCs are isolated by Ficoll density gradient centrifugation and cells count and the relative mean volume is performed with a Coulter(®) instrument. Extraction of drugs from PBMCs pellets was obtained with methanol:water (70:30, v/v), with quinoxaline added as internal standard, after a sonication step. Supernatant was dried and then dissolved in water/acetonitrile (60/40, v/v), before injection into a 2.1 mm×150 mm Atlantis(®) T3 3μ column. Chromatographic separations were performed using a gradient program with a mixture of water (0.05% formic acid), as mobile phase A and acetonitrile (0.05% formic acid), as mobile phase B. Analytes quantification was performed by electro-spray ionisation-single quadrupole mass spectrometry using the selected ion recording (SIR) detection mode. The positive ionization was used for the HIV protease inhibitors (PIs) indinavir, saquinavir, nelfinavir, nelfinavir M8 metabolite, amprenavir, darunavir, atazanavir, ritonavir, lopinavir, tipranavir, the integrase inhibitor (II) raltegravir and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine and etravirine, while the negative ionization is applied for efavirenz. The calibration curves were built using blank PBMCs spiked with antiretroviral drugs at concentrations ranging from 0.1 to 32 ng/mL (1-320 ng/mL for tipranavir) and fitted to a quadratic regression model weighted by 1/X. The mean extraction recovery for all PIs, II and NNRTIs was always above 82%. The method was precise, with a range of intra/inter-day percent standard deviation within 2.6-14.8%, and accurate with mean of percent coefficient of variation (CV%) from nominal values -7.85 to +9.7%. Each drug concentration evaluated was expressed in ng/mL and optimized using each patient medium corpuscolar volume and cell number. This analytical method is routinely used in our clinical research center for the assessment of intracellular levels of all PIs, raltegravir and NNRTIs commercially available at present., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The identification of transporters of the HIV integrase inhibitor raltegravir could be a factor in an understanding of the pharmacokinetic-pharmacodynamic relationship and reported drug interactions of raltegravir. Here we determined whether raltegravir was a substrate for ABCB1 or the influx transporters SLCO1A2, SLCO1B1, SLCO1B3, SLC22A1, SLC22A6, SLC10A1, SLC15A1, and SLC15A2. Raltegravir transport by ABCB1 was studied with CEM, CEM(VBL100), and Caco-2 cells. Transport by uptake transporters was assessed by using a Xenopus laevis oocyte expression system, peripheral blood mononuclear cells, and primary renal cells. The kinetics of raltegravir transport and competition between raltegravir and tenofovir were also investigated using SLC22A6-expressing oocytes. Raltegravir was confirmed to be an ABCB1 substrate in CEM, CEM(VBL100), and Caco-2 cells. Raltegravir was also transported by SLC22A6 and SLC15A1 in oocyte expression systems but not by other transporters studied. The K(m) and V(max) for SLC22A6 transport were 150 μM and 36 pmol/oocyte/h, respectively. Tenofovir and raltegravir competed for SLC22A6 transport in a concentration-dependent manner. Raltegravir inhibited 1 μM tenofovir with a 50% inhibitory concentration (IC(50)) of 14.0 μM, and tenofovir inhibited 1 μM raltegravir with an IC(50) of 27.3 μM. Raltegravir concentrations were not altered by transporter inhibitors in peripheral blood mononuclear cells or primary renal cells. Raltegravir is a substrate for SLC22A6 and SLC15A1 in the oocyte expression system. However, transport was limited compared to endogenous controls, and these transporters are unlikely to have a great impact on raltegravir pharmacokinetics.

Background: Use of unboosted atazanavir (ATV) with tenofovir disoproxil fumarate (TDF), although attractive from a clinical view point, has not been tested in trials and is not currently recommended because of the risk of suboptimal ATV pharmacokinetics (PK). In order to improve ATV exposure, plasma and intracellular (IC) PK of ATV in patients administered with ATV 400 mg once daily and TDF/emtricitabine (FTC) and switched to ATV 200 mg twice daily were studied., Methods: On day 0, 10 subjects on ATV 400 mg plus TDF/FTC once daily underwent intensive plasma and IC PK evaluation and bilirubin measurement. Patients were subsequently switched to ATV 200 mg twice daily for 10 days. On day 11, they once again underwent intensive PK and bilirubin evaluation., Results: Switch to 200 mg twice daily led (in plasma) to a significant increase of the observed concentration at the end of dosing interval (C(trough); ratio twice daily/once daily 2.20; P=0.005), with a decrease from 60% to 20% of suboptimal values, a significant decrease of the maximum concentration (C(max); ratio twice daily/once daily 0.47; P=0.022), whereas no differences of other PK parameters or bilirubin were observed. IC ATV concentrations at 400 once daily showed higher C(trough) (ratio peripheral blood mononuclear cells [PBMCs]/plasma 2.86; P=0.005) and longer half-life (ratio PBMCs/plasma 1.44; P=0.007) as compared with plasma. After the switch, IC ATV accumulation showed changes similar to plasma., Conclusions: Switch to 200 mg twice daily appeared to optimize plasma and IC ATV PK, by increasing the determinant of efficacy (C(trough)) and decreasing C(max), without significant effect on total ATV plasma exposure and bilirubin. Dosage of 200 mg might provide an option to patients showing suboptimal ATV exposure with standard unboosted dosing.

A bioanalytical method for the determination of most commonly prescribed protease inhibitors (saquinavir, atazanavir, amprenavir, darunavir, lopinavir and ritonavir) and non-nucleoside reverse transcriptase inhibitors (etravirine, efavirenz and nevirapine) was developed, modifying our previous HPLC-MS chromatographic run, validated and a complete short and long term stability evaluation was carried out. One hundred microlitres of plasma were distributed on a collection glass paper filter (Glass-Microfibre from Sartorius), then the filter underwent thermal treatment, both for drying and for HIV inactivation, and stored at room temperature, 4 degrees C and -20 degrees C. The analytes were extracted from the filter disc using tert-butylmethylether with basic pH, after the addition of the internal standards quinoxaline. The extract was dried, reconstituted and the chromatographic separation was performed on a reversed-phase C-18 column (150 mm x 2.0 mm) and the analytes were quantified using a single quadrupole mass spectrometer. The method was validated considering the concentration ranges encountered in clinical trials and the routine clinical practice. The assay was linear over the concentration ranges tested. Accuracies ranged from 92.1% to 111.9% and intra-day and inter-day relative standard deviation for all quality control levels ranged from 0.2 to 12.9 and 3.1 to 14.4, respectively. Analytes in dried plasma spots were stable for longer time when dried/inactivation step was carried out before storage compared to samples not dried/inactivated before the analysis. The dried/inactivation step allows shipment of samples at room temperature without any risks, therefore the developed and validated method enables an easy and cheap sample shipment for therapeutic drug monitoring and pharmacokinetic studies., (2010 Elsevier B.V. All rights reserved.)

Clinical pharmacokinetic studies of antiretrovirals require accurate and precise measurement of plasma drug concentrations. Here we describe a simple, fast and sensitive HPLC-MS/MS method for determination of the commonly used protease inhibitors (PI) amprenavir, atazanavir, darunavir, lopinavir, ritonavir, saquinavir and the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, as well as the more recent antiretrovirals, the CCR5 antagonist maraviroc and the "second generation" NNRTI etravirine and rilpivirine. An internal standard (quinoxalone; QX) was added to plasma aliquots (100 microl) prior to protein precipitation with acetonitrile (500 microl) followed by centrifugation and addition of 0.05% formic acid (200 microl) to the supernatant. Chromatographic separation was achieved using a gradient (acetonitrile and 0.05% formic acid) mobile phase on a reverse-phase C18 column. Detection was via selective reaction monitoring (SRM) operating in positive ionization mode on a triple-quadrupole mass spectrometer. All compounds eluted within a 5 min run time. Calibration curves were validated over concentration ranges reflecting therapeutic concentrations observed in HIV-infected patients from pharmacokinetic data reported in the literature. Correlation coefficients (r2) exceeded 0.998. Inter- and intra-assay variation ranged between 1% and 10% and % recovery exceeded 90% for all analytes. The method described is being successfully applied to measure plasma antiretroviral concentrations from samples obtained from clinical pharmacokinetic studies., (Copyright 2010 Elsevier B.V. All rights reserved.)

A new solid-phase extraction (SPE) method has been developed and validated on a liquid chromatography (LC) coupled with a mass spectrometer for the determination of plasma concentrations of tenofovir (TNF) and emtricitabine (FTC) in HIV infected patients. Chromatographic separation was achieved with a gradient (acetonitrile and water with formic acid 0.05%) on an Atlantis 4.6 mm x 150 mm, reversed phase analytical column. Detection of TNF, FTC, and internal standard (IS) was achieved by electrospray ionization mass spectrometry (ESI-MS) in the positive ion mode. Calibration ranged from 15.6 to 4000 ng/mL for TNF and 11.7 to 3000 ng/mL for FTC. Plasma was analyzed, and the limit of quantitation was 15.6 ng/mL for TNF and 11.7 ng/mL for FTC; limit of detection was 2 ng/mL for TNF and 1.5 ng/mL for FTC. Mean recovery of TNF, FTC, and IS were 46.5% [relative standard deviation (RSD): 8.8%] and 88.8% (RSD: 1.0%), and 81.7% (RSD: 3.1%), respectively. The method did not show any significant interference with antiretrovirals or other concomitant drugs administered to patients, and no significant "matrix effects" were observed. The method was applied for the determination of antiretroviral plasma concentration of HIV-positive patients treated with FTC and/or TNF, in combination with various other antiretrovirals.

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.

Aims: The impact of ageing on antiretroviral pharmacokinetics remains uncertain, leading to missing dosing recommendations for elderly people living with human immunodeficiency virus (HIV: PLWH). The objective of this study was to investigate whether ageing leads to clinically relevant pharmacokinetic changes of antiretrovirals that would support a dose adjustment based on the age of the treated PLWH. Methods: Plasma concentrations for 10 first‐line antiretrovirals were obtained in PLWH ≥55 years, participating in the Swiss HIV Cohort Study, and used to proof the predictive performance of our physiologically based pharmacokinetic (PBPK) model. The verified PBPK model predicted the continuous effect of ageing on HIV drug pharmacokinetics across adulthood (20–99 years). The impact of ethnicity on age‐related pharmacokinetic changes between whites and other races was statistically analysed. Results: Clinically observed concentration–time profiles of all investigated antiretrovirals were generally within the 95% confidence interval of the PBPK simulations, demonstrating the predictive power of the modelling approach used. The predicted decline in drug clearance drove age‐related pharmacokinetic changes of antiretrovirals, resulting in a maximal 70% [95% confidence interval: 40%, 120%] increase in antiretrovirals exposure across adulthood. Peak concentration, time to peak concentration and apparent volume of distribution were predicted to be unaltered by ageing. There was no statistically significant difference of age‐related pharmacokinetic changes between studied ethnicities. Conclusion: Dose adjustment for antiretrovirals based on the age of male and female PLWH is a priori not necessary in the absence of severe comorbidities considering the large safety margin of the current first‐line HIV treatments. [ABSTRACT FROM AUTHOR]