Elodie Valade

Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients

ABSTRACT The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CLCR), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC0-24) was 12.5 mg · h/liter for patients with normal renal function (CLCR, >80 ml/min), 14.7 mg · h/liter for patients with mild renal impairment (CLCR, 79 to 50 ml/min), and 17.9 mg · h/liter for patients with moderate renal impairment (CLCR, 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC0-48, 17.2 mg · h/liter) than for patients with normal renal function (median AUC0-48, 25.6 mg · h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function.

Physiologically‐based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women

AIM Physiological changes during pregnancy can affect drug disposition. Anticipating these changes will help to maximize drug efficacy and safety in pregnant women. Our objective was to determine if physiologically-based pharmacokinetics (PBPK) can accurately predict changes in the disposition of renally excreted antiretroviral drugs during pregnancy. METHODS Whole body PBPK models were developed for three renally excreted antiretroviral drugs, tenofovir (TFV), emtricitabine (FTC) and lamivudine (3TC). To assess the impact of pregnancy on PK, time-varying pregnancy-related physiological parameters available within the p-PBPK Simcyp software package were used. Renal clearance during pregnancy followed glomerular filtration changes with or without alterations in secretion. PK profiles were simulated and compared with observed data, i.e. area under the curves (AUC), peak plasma concentrations (Cmax ) and oral clearances (CL/F). RESULTS PBPK models successfully predicted TFV, FTC and 3TC disposition for non-pregnant and pregnant populations. Both renal secretion and filtration changed during pregnancy. Changes in renal clearance secretion were related to changes in renal plasma flow. The maximum clearance increases were approximately 30% (TFV 33%, FTC 31%, 3TC 29%). CONCLUSIONS Pregnancy PBPK models are useful tools to quantify a priori the drug exposure changes during pregnancy for renally excreted drugs. These models can be applied to evaluate alternative dosing regimens to optimize drug therapy during pregnancy.

Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models

AIMS Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. METHODS Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. RESULTS Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo. CONCLUSION The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.

Prediction of drug clearance in children

The pediatric population is often exposed to drugs without sufficient knowledge about pharmacokinetics. The prediction of accurate clearance values in children, especially in neonates and infants, will improve the rational in dosing decisions. Drug clearances from birth to adulthood were compiled after a systematic review of pharmacokinetic reports. The analysis was performed using NONMEM. Clearance predictions were then evaluated by external validation. Prediction errors were also compared with those obtained from weight‐based allometric scaling and physiologically based clearance (PBCL) models. For the analysis, 17 and 15 drugs were used for model building and external validation, respectively. A model based on the adult drug clearance value and taking into account both weight and age was retained. Age‐related maturation of clearance reached 90% of the adult value within 1.5 years of life. For children less than 2 years old, allometric scaling alone systematically overestimated clearances. Accounting for age improved the clearance prediction in the 6 months–2 years age group (prediction error < 25%). Predictions obtained from the PBCL approach were close to our results. This analysis established a single equation using the adult clearance value as well as individual age and weight to predict drug clearance in children older than 6 months.

Modified renal function in pregnancy: impact on emtricitabine pharmacokinetics

AIMS The aims were to describe emtricitabine (FTC) pharmacokinetics in a large population of pregnant women during the different trimesters of pregnancy, and to explain FTC pharmacokinetic variability during pregnancy. METHODS FTC plasma concentrations were measured in 103 non-pregnant and 83 pregnant women, including women in the different trimesters of pregnancy and on the day of delivery. A total of 457 plasma concentrations were available for analysis. A population pharmacokinetic model was developed with Monolix 4.1.3. RESULTS FTC pharmacokinetics was best described by a two compartment model. The effect of creatinine clearance on apparent elimination clearance (CL/F) was significant. CL/F in pregnant women was significantly higher compared with non-pregnant women (geometric mean 24.1 vs 20.5 l h(-1) , P < 0.001), reflecting a modified renal function. FTC daily exposures (AUC) during pregnancy were lower than AUC in non-pregnant women, regardless of the trimester of pregnancy. FTC AUC geometric means were 8.38 mg l(-1 ) h in the second trimester of pregnancy, 8.16 mg l(-1 ) h in the third trimester of pregnancy, 8.30 mg l(-1 ) h on the day of delivery and 9.77 mg l(-1 ) h in non-pregnant women. FTC concentrations 24 h after administration were lower in pregnant women compared with non-pregnant women (0.054 vs. 0.079 mg l(-1) , P < 0.001) but still above the inhibitory concentration 50%. CONCLUSIONS FTC CL/F was increased by 18% during pregnancy, reflecting a modified renal function with 50% increase in estimated glomerular filtration rate. However, the impact of this modified renal function on FTC pharmacokinetics was not sufficiently large to consider dose adjustments during pregnancy.

Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

ABSTRACT We aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) were higher in SP than in BP (median AUC0–24, 38.04 and 12.95 mg · liter−1 · h, respectively). The median (range) SP-to-BP AUC0–24 ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC0–24 ratios were lower than 1. The impact of FTC SP AUC0–24 or FTC SP-to-BP AUC0–24 ratio on spVL detection was not significant (P = 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.

Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

ABSTRACT The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy.

Population Pharmacokinetics of Abacavir in Pregnant Women

ABSTRACT For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy.

Development and validation of a LC–MS/MS method for the quantification of tenofovir and emtricitabine in seminal plasma

Accurate and sensitive liquid-chromatography tandem mass spectrometry method for the quantification of tenofovir and emtricitabine in seminal plasma has been developed and full validated. Molecules were separated by high-performance liquid chromatography on an Atlantis T3 C18 column using a gradient of deionized water and methanol, including 0.05% formic acid (250μl/min) and detected by electrospray ionisation/tandem mass spectrometry in positive ion mode. The method was validated over a clinical range of 3.13-1000ng/mL for tenofovir and 6.25-2000ng/mL for emtricitabine. Inter and intra-assay precisions were <9.37% for tenofovir and<10.88% for emtricitabine, and accuracies were between 0.48% and 8.43% for tenofovir, and between 0.64% and 13.87% for emtricitabine. The developed method was successfully applied for analysing tenofovir and emtricitabine concentrations in seminal plasma samples from a clinical study. The use of tandem mass spectrometry can be a suitable method for the analysis of this kind of matrices, providing high sensitivity and specificity to the analysis.

Maternal and fetal zidovudine pharmacokinetics during pregnancy and labour: too high dose infused at labour?

AIMS The main goal of the study was to describe the pharmacokinetics of maternal zidovudine (ZDV) administration during pregnancy and labour and to evaluate their impact on fetal concentrations and exposures. METHODS A total of 195 HIV-infected pregnant and non-pregnant women aged 16-59 years were included and 273 maternal and 79 cord blood ZDV concentrations were collected. A population pharmacokinetic model was developed to describe ZDV concentrations as a function of time in the mother and the fetus. Fetal exposures resulting from maternal oral administration and infusion were estimated and compared with therapeutic exposures (3-5 mg l(-1)  h) and to exposure providing higher risk of toxicity (>8.4 mg l(-1)  h). Different protocols for ZDV administration during labour were simulated. RESULTS The median fetal exposure and the percentage of children with values above 8.4 mg l(-1)  h were 3.20 mg l(-1)  h and 0% after maternal oral administration, respectively, and 9.71 mg l(-1)  h and 51% after maternal infusion during labour. Two options were considered to reduce fetal exposure during labour: (i) maternal infusion rates could be 1 mg kg(-1)  h(-1) during 1 h followed by 0.5 mg kg(-1)  h(-1) and (ii) the mother could only take oral ZDV every 5 h from start of labour until delivery with her neonate having their first ZDV dose as soon as possible after birth. CONCLUSIONS Zidovudine exposures are very important during labour and during the first days of a neonates life. Maternal ZDV dose should be reduced in addition to the neonate doses reduction already proposed.