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ABSTRACTIntroduction: Depression affects 300 million individuals worldwide. While selective serotonin reuptake inhibitors (SSRI) are one of the first-line pharmacological treatments of major depression in the general population, there is still uncertainty regarding their potential benefits and risks during pregnancy.Areas covered: Outcomes requisite for a proper risk/benefit assessment of SSRI in pregnancy and lactation were considered: (a) potential risks associated with untreated depression, (b) effectiveness of different treatment options of depression, (c) potential risks associated with SSRI.Expert opinion: Despite the growing amount of literature on SSRI use during pregnancy, no new trials assessing the benefits of SSRIs on maternal depression were found. In the light of new data regarding the potential risks, depressed SSRI-treated pregnant women and their children seem at increased risk for several complications (mostly of small absolute risk). The interpretation of these findings remains quite similar to our previous review as the available methodology does not allow to disentangle the potential effect of SSRIs from those of the disease itself or/and of its unmeasured associated risk factors. Thus, in pregnant or lactating women who require a pharmacological treatment, SSRIs can still be considered as appropriate when effective as the abundant data support their relative safety.

Background Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets.Methods 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow-up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analysed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20–40 ng/ml during 12 months of follow-up and several dosage regimens were evaluated by simulation.Results A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharma-cokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/ritonavir and the genetic variant in GC(rs2282679) on 25(OH)D concentrations. 11% of the inter-individual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates, and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300,000 IU two times per year.Conclusions This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.

Introduction:Psychiatric disorders are among the leading causes of disability in Western societies. Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressant drugs during pregnancy and the postpartum period. Over the last decade, conflicting findings regarding the safety of SSRI drugs during pregnancy and lactation have questioned whether such treatments should be used during this period.Areas covered:We discuss the main criteria that should be considered in the risk/benefit assessment of SSRI treatment in pregnant and/or breastfeeding patients (i.e., risks associated with SSRI use and with untreated depression as well as therapeutic benefits of SSRI and some alternative treatment strategies). For each criterion, available evidence has been synthesized and stratified by methodological quality as well as discussed for clinical impact.Expert opinion:Currently, it is impossible for most of the evaluated outcomes to distinguish between the effects related to the mother’s underlying disease and those inherent to SSRI treatment. In women suffering from major depression and responding to a pharmacological treatment, introduction or continuation of an SSRI should be encouraged in order to prevent maternal complications and to preserve maternal–infant bonding. The choice of the right drug depends above all on individual patient characteristics such as prior treatment response, diagnoses and comorbid conditions.

ABSTRACTArtemether-lumefantrine (AL) is the first-line treatment for uncomplicated malaria in the second and third trimesters of pregnancy. Its efficacy during pregnancy has recently been challenged due to altered pharmacokinetic (PK) properties in this vulnerable group. The aim of this study was to determine the PK profile of AL in pregnant and nonpregnant women and assess their therapeutic outcome. Thirty-three pregnant women and 22 nonpregnant women with malaria were treated with AL (80/480 mg) twice daily for 3 days. All patients provided five venous plasma samples for drug quantification at random times over 7 days. Inter- and intraindividual variability was assessed, and the effects of covariates were quantified using a nonlinear mixed-effects modeling approach (NONMEM). A one-compartment model with first-order absorption and elimination with linear metabolism from drug to metabolite fitted the data best for both arthemether (AM) and lumefantrine (LF) and their metabolites. Pregnancy status and diarrhea showed a significant influence on LF PK. The relative bioavailability of lumefantrine and its metabolism rate into desmethyl-lumefantrine were, respectively, 34% lower and 78% higher in pregnant women than in nonpregnant patients. The overall PCR-uncorrected treatment failure rates were 18% in pregnant women and 5% in nonpregnant women (odds ratio [OR] = 4.04; Pvalue of 0.22). A high median day 7 lumefantrine concentration was significantly associated with adequate clinical and parasitological response (P= 0.03). The observed reduction in the relative bioavailability of lumefantrine in pregnant women may explain the higher treatment failure in this group, mostly due to lower posttreatment prophylaxis. Hence, a modified treatment regimen of malaria in pregnancy should be considered.

Suite à la tragédie de la thalidomide, la recherche en pharmacothérapie chez la femme enceinte s’est concentrée avant tout sur la sécurité des médicaments pour l’enfant à naître et très peu sur l’efficacité ou la sécurité des traitements pour la mère. Les changements physiologiques importants pendant la grossesse peuvent pourtant influencer la pharmacocinétique des médicaments et ainsi compromettre leur efficacité et/ou sécurité. Le suivi thérapeutique pharmacologique (STP) permettrait d’optimiser l’efficacité de certains traitements, tout en minimisant le risque potentiel de toxicité materno-fœtale. Toutefois, en raison de l’absence d’études concentration-réponse chez la femme enceinte, le STP ne peut reposer actuellement que sur l’évaluation individuelle (rapporté à une concentration efficace prégrossesse) et reste réservé uniquement à certaines situations particulières, incluant notamment des signes de toxicité ou une inefficacité inexpliquée.

ABSTRACTNew directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real-time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy.

The frequently prescribed antidementia drug galantamine is extensively metabolized by the enzymes cytochrome P450 (CYP) 2D6 and CYP3A and is a substrate of the P-glycoprotein. We aimed to study the relationship between genetic variants influencing the activity of these enzymes and transporters with galantamine steady state plasma concentrations.

Several population pharmacokinetic (PPK) analyses of the anticancer drug imatinib have been performed to investigate different patient populations and covariate effects. The present analysis offers a systematic qualitative and quantitative summary and comparison of those. Its primary objective was to provide useful information for evaluating the expectednessof imatinib plasma concentration measurements in the frame of therapeutic drug monitoring. The secondary objective was to review clinically important concentration-effect relationships to provide help in evaluating the potential suitabilityof plasma concentration values. Nine PPK models describing total imatinib plasma concentration were identified. Parameter estimates were standardized to common covariate values whenever possible. Predicted median exposure (Cmin) was derived by simulations and ranged between models from 555 to 1388 ngmL (grand median: 870 ngmL and interquartile “reference” range: 520–1390 ngmL). Covariates of potential clinical importance (up to 30 change in pharmacokinetic predicted by at least 1 model) included body weight, albumin, 1acid glycoprotein, and white blood cell count. Various other covariates were included but were statistically not significant or seemed clinically less important or physiologically controversial. Concentration–response relationships had more importance below the average reference range and concentration–toxicity relationships above. Therapeutic drug monitoring–guided dosage adjustment seems justified for imatinib, but a formal predictive therapeutic range remains difficult to propose in the absence of prospective target concentration intervention trials. To evaluate the expectednessof a drug concentration measurement in practice, this review allows comparison of the measurement either to the average reference range or to a specific range accounting for individual patient characteristics. For future research, external PPK model validation or meta-model development should be considered.

(S)-Methadone, metabolized mainly by CYP2B6, shows a wide interindividual variability in its pharmacokinetics and pharmacodynamics.

Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals.

ABSTRACTThe pharmacogenetics of antimalarial agents are poorly known, although the application of pharmacogenetics might be critical in optimizing treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effects of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme genes (CYP, namely, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) and the N-acetyltransferase 2 gene (NAT2) on the pharmacokinetics of artemisinin-based combination therapies in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9*3, CYP2D6*10(100C→T), CYP3A5*3, NAT2*6, and NAT2*7. In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6*17(1023C→T and 2850C→T), CYP3A4*1B, NAT2*5, and NAT2*14. For 8 SNPs, no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies in different populations, ideally with the same artemisinin-based combination therapies, are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials.

ABSTRACTThe objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV+) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV+than in healthy individuals. UGT1A9*3was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Introduction:Besides therapeutic effectiveness, drug tolerability is a key issue for treatments that must be taken indefinitely. Given the high prevalence of toxicity in HIV therapy, the factors implicated in drug-induced morbidities should be identified in order to improve the safety, tolerability and adherence to the treatments. Current approaches have focused almost exclusively on parent drug concentrations; whereas recent evidence suggests that drug metabolites resulting from complex genetic and environmental influences can also contribute to treatment outcome. Pharmacogenetic variations have shown to play a relevant role in the variability observed in antiretroviral drug exposure, clinical response and sometimes toxicity. The integration of pharmacokinetic, pharmacogenetic and metabolic determinants will more probably address current therapeutic needs in patients.Areas covered:This review offers a concise description of three classes of antiretroviral drugs. The review looks at the metabolic profile of these drugs and gives a comprehensive summary of the existing literature on the influence of pharmacogenetics on their pharmacokinetics and metabolic pathways, and the associated drug or metabolite toxicity.Expert opinion:Due to the high prevalence of toxicity and the related risk of low adherence to the treatments, association of kinetic, genetic and metabolic markers predictive of therapeutic or toxicity outcomes could represent a more complete approach for optimizing antiretroviral therapy.

An ADME (absorption, distribution, metabolism and excretion) – pharmacogenetics association study may identify functional variants relevant to the pharmacokinetics of lopinavir coformulated with ritonavir (LPVr), a first-line anti-HIV agent.

The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function.

ABSTRACTAtazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h−1(CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.

A major goal in clinical pharmacology is the quantitative prediction of drug effects. The field of pharmacokinetic–pharmacodynamic (PK/PD) modelling has made many advances from the basic concept of the dose–response relationship to extended mechanism-based models. The purpose of this article is to review, from a historical perspective, the progression of the modelling of the concentration–response relationship from the first classic models developed in the mid-1960s to some of the more sophisticated current approaches. The emphasis is on general models describing key PD relationships, such as: simple models relating drug dose or concentration in plasma to effect, biophase distribution models and in particular effect compartment models, models for indirect mechanism of action that involve primarily the modulation of endogenous factors, models for cell trafficking and transduction systems. We show the evolution of tolerance and time-variant models, non- and semi-parametric models, and briefly discuss population PK/PD modelling, together with some example of more recent and complex pharmacodynamic models for control system and nonlinear HIV-1 dynamics. We also discuss some future possible directions for PK/PD modelling, report equations for general classes of novel semi-parametric models, as well as describing two new classes, additive or set-point, of regulatory, additive feedback models in their direct and indirect action variantsA major goal in clinical pharmacology is the quantitative prediction of drug effects. The field of pharmacokinetic–pharmacodynamic (PK/PD) modelling has made many advances from the basic concept of the dose–response relationship to extended mechanism-based models. The purpose of this article is to review, from a historical perspective, the progression of the modelling of the concentration–response relationship from the first classic models developed in the mid-1960s to some of the more sophisticated current approaches. The emphasis is on general models describing key PD relationships, such as: simple models relating drug dose or concentration in plasma to effect, biophase distribution models and in particular effect compartment models, models for indirect mechanism of action that involve primarily the modulation of endogenous factors, models for cell trafficking and transduction systems. We show the evolution of tolerance and time-variant models, non- and semi-parametric models, and briefly discuss population PK/PD modelling, together with some example of more recent and complex pharmacodynamic models for control system and nonlinear HIV-1 dynamics. We also discuss some future possible directions for PK/PD modelling, report equations for general classes of novel semi-parametric models, as well as describing two new classes, additive or set-point, of regulatory, additive feedback models in their direct and indirect action variants

CHF3381 (2-[(2,3-dihydro-1H-inden-2-yl)amino]acetamide monohydrochloride) is a new N-methyl-D-aspartate antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor in development for the treatment of neuropathic pain. This study developed a mechanistic model to describe the pharmacokinetics of CHF3381 and of its two metabolites, the relationship with MAO-A activity and heart rate. Doses of 100, 200, and 400 mg twice daily for 2 weeks were administered orally to 36 subjects. MAO-A activity was estimated by measuring concentrations of 3,4-dihydroxyphenylglycol (DHPG), a stable metabolite of norepinephrine. A multicompartment model with time-dependent clearance was used to describe the kinetics of CHF3381 and metabolite concentrations. Estimated pharmacokinetic parameters were CL (41.2 to 27.4 l/h over the study), V (131 liters), Q (1.7 l/h), V(p) (36 liters), and k(a) (1.85 h(-1)). The relationship between CHF3381 and DHPG or heart rate was described using an indirect or a direct linear model, respectively. The production rate of DHPG (k(in)) was 2540 ng . h(-1), reduced by 63% at maximal CHF3381 concentrations. EC(50) was 1670 mug/l, not significantly different from the in vitro IC(50). The increase in heart rate due to CHF3381 was 0.0055 bpm/micro(g l-1). CHF3381 produces a concentration-dependent decrease in DHPG plasma concentrations, whose magnitude increased after multiple twice-a-day regimens for 14 days.

ABSTRACTIndinavir is currently used at a fixed dose of 800 mg either three times a day or twice a day in combination with 100 mg of ritonavir. Dosage individualization based on plasma concentration monitoring might, however, be indicated. This study aimed to assess the pharmacokinetic profile of indinavir in patients infected with human immunodeficiency virus to characterize interpatient and intrapatient variability and to build up a Bayesian approach for dosage adaptation. A population analysis was performed with the NONMEM computer program with 569 plasma samples from a cohort of 239 unselected patients receiving indinavir. A one-compartment model with first-order absorption was adapted, and the influences of clinical characteristics on oral clearance (CL) and distribution volume (V) were examined. Predicted average drug exposure and trough and peak concentrations were derived for each patient and correlated with efficacy and toxicity markers. The population estimates of CL were 32.4 liters/h for female and 42.0 liters/h for male patients; oral Vwas 65.7 liters; and the rate constant of absorption (Ka) was 1.0 h−1. CL decreased by 63% with ritonavir intake and was moderately correlated to body weight. Both interpatient variability, best assigned to oral CL (coefficient of variation [CV], 39%) and Ka(CV, 67%), and intrapatient variability were large (CV, 41%; standard deviation, 670 μg/liter). In conclusion, initial indinavir dosage should be decided according to ritonavir intake and sex, prior to plasma concentration measurements. The high interpatient pharmacokinetic variability represents an argument for therapeutic drug monitoring.

Objective: The reverse transcriptase inhibitor efavirenz is currently used at a fixed dose of 600 mg/d. However, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the efavirenz pharmacokinetic profile and interpatient versus intrapatient variability in patients who are positive for human immunodeficiency virus, to explore the relationship between drug exposure, efficacy, and central nervous system toxicity and to build up a Bayesian approach for dosage adaptation.Methods: The population pharmacokinetic analysis was performed by use of NONMEM based on plasma samples from a cohort of unselected patients receiving efavirenz. With the use of a 1-compartment model with first-order absorption, the influence of demographic and clinical characteristics on oral clearance and oral volume of distribution was examined. The average drug exposure during 1 dosing interval was estimated for each patient and correlated with markers of efficacy and toxicity. The population kinetic parameters and the variabilities were integrated into a Bayesian equation for dosage adaptation based on a single plasma sample.Results: Data from 235 patients with a total of 719 efavirenz concentrations were collected. Oral clearance was 9.4 L/h, oral volume of distribution was 252 L, and the absorption rate constant was 0.3 h−1. Neither the demographic covariates evaluated nor the comedications showed a clinically significant influence on efavirenz pharmacokinetics. A large interpatient variability was found to affect efavirenz relative bioavailability (coefficient of variation, 54.6%), whereas the intrapatient variability was small (coefficient of variation, 26%). An inverse correlation between average drug exposure and viral load and a trend with central nervous system toxicity were detected. This enabled the derivation of a dosing adaptation strategy suitable to bring the average concentration into a therapeutic target from 1000 to 4000 μg/L to optimize viral load suppression and to minimize central nervous system toxicity.Conclusions: The high interpatient and low intrapatient variability values, as well as the potential relationship with markers of efficacy and toxicity, support the therapeutic drug monitoring of efavirenz. However, further evaluation is needed before individualization of an efavirenz dosage regimen based on routine drug level monitoring should be recommended for optimal patient management.

The objective of this study was to investigate the population pharmacokinetics (PK) of amoxicillin in ICU burn patients and the optimal dosage regimens. This was a prospective study involving 21 consecutive burn patients receiving amoxicillin.

ABSTRACTOptimal dosing of gentamicin in neonates is still a matter of debate despite its common use. We identified gentamicin dosing regimens from eight international guidelines and seven Swiss neonatal intensive care units. The dose per administration, the dosing interval, the total daily dose, and the demographic characteristics between guidelines were compared. There was considerable variability with respect to dose (4 to 6 mg/kg), dosing interval (24 h to 48 h), total daily dose (2.5 to 6 mg/kg/day), and patient demographic characteristics that were used to calculate individualized dosing regimens. A model-based simulation study in 1071 neonates was performed to determine the achievement of efficacious peak gentamicin concentrations according to predefined MICs (Cmax/MIC ≥ 10) and safe trough concentrations (Cmin≤ 2 mg/liter) with recommended dosing regimens. MIC targets of 0.5 and 1 mg/liter were used. Dosing optimization was performed giving priority to the first day of treatment and with the goal of simplifying dosing. Current gentamicin neonatal guidelines allow to achieve effective peak concentrations for MICs ≤ 0.5 mg/liter but not higher. Model-based simulations indicate that to attain peak gentamicin concentrations of ≥10 mg/liter, a dose of 7.5 mg/kg should be administered using an extended dosing interval regimen. Trough concentrations of ≤2 mg/liter can be maintained with a dosing interval of 36 to 48 h in neonates according to gestational and postnatal age. For treatment beyond 3 days, therapeutic drug monitoring is advised to maintain adequate serum concentrations.

ABSTRACTRilpivirine (RPV), the latest nonnucleoside reverse transcriptase inhibitor active against HIV-1, is prescribed in a standard dosage of 25 mg once a day in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The aim of this observational study was to characterize the RPV pharmacokinetic profile, to quantify interpatient variability, and to identify potential factors that could influence drug exposure. RPV concentration data were collected from HIV-infected patients as part of routine therapeutic drug monitoring performed in our center (Laboratory of Clinical Pharmacology). A population pharmacokinetic analysis was performed with NONMEM by comparing various structural models. The influence of demographic and clinical covariates, as well as frequent genetic polymorphisms in 5 genes (CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, UGT1A1*28, and UGT1A4*2), on RPV elimination was explored. A total of 325 plasma concentration measurements were obtained from 249 HIV-positive patients. Plasma concentrations ranged from 12 to 255 ng/ml. A one-compartment model with zero-order absorption best characterized RPV pharmacokinetics. The average RPV clearance (CL) was 11.7 liters/h, the average volume of distribution was 401 liters, and the mean absorption time was 4 h. The interinterindividual variability (IIV) for CL was estimated to be 33%. None of the available demographic or genetic covariates showed any influence on RPV pharmacokinetics, but 29% of the patients were predicted to present minimal concentrations below the recently identified target cutoff value of 50 ng/ml. The variability in RPV pharmacokinetics appears to be lower than that for most other antiretroviral drugs. However, under the standard regimen of 25 mg daily, a significant number of patients might be underdosed. It remains to be investigated whether the underexposure has an impact on the development of resistance while patients are on maintenance therapy.