Sihem Benaboud

Pregnancy-Related Effects on Tenofovir Pharmacokinetics: a Population Study with 186 Women

ABSTRACT According to the European AIDS Clinical Society, tenofovir disoproxil fumarate can be used in HIV-infected pregnant women if started prior to pregnancy, although no data are available on the pharmacokinetics of tenofovir (TFV) during pregnancy. The aim of this study was to describe TFV pharmacokinetics in HIV-infected women and to evaluate the effect of pregnancy on TFV disposition. Samples were collected according to a therapeutic drug monitoring in 186 women, including 46 pregnant women treated with TFV and retrospectively analyzed by a population approach. TFV pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. The mean population parameter estimates (between-subject variability) were as follows: absorption rate constant, 0.56 h−1; elimination clearance, 59.9 liters h−1 (0.436); central volume of distribution, 552 liters (1.96); intercompartmental clearance, 172 liters/h; and peripheral volume of distribution, 1,390 liters. Pregnant women had a 39% higher apparent clearance compared to nonpregnant women. Apparent clearance significantly decreased with age. In order to obtain an exposure similar to the known exposure in adults and guarantee similar trough concentrations (Cmin) as observed in adults, an increase in the TFV dose should be considered for women from the second trimester to delivery.

Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates.

ABSTRACT The aim of the present study was to describe the nevirapine (NVP) pharmacokinetics (PK) in pregnant women and their neonates and to evaluate the transplacental drug transfer and administration scheme for the prevention of mother-to-child transmission. Thirty-eight HIV-1-infected pregnant women were administered one tablet of NVP (200 mg) and two tablets of tenofovir-emtricitabine (Truvada) at the initiation of labor. Children were given NVP syrup (2 mg/kg of body weight) as a single dose (sdNVP) on the first day of life. By pair, NVP concentrations were measured in 11 maternal, 1 cord blood, and 2 neonatal plasma samples and analyzed by a population approach. A one-compartment model was used for mothers and neonates; the absorption rate constants for mothers and neonates were 0.95 h−1 (intersubject variability, 111%) and 0.39 h−1, respectively; the apparent elimination clearances were 1.42 liter·h−1 (intersubject variability, 22%) and 0.035 liter·h−1, respectively; and apparent volumes of distribution were 87.3 liters (intersubject variability, 25%) and 5.65 liters, respectively. An effect compartment was linked to maternal circulation by mother-to-cord and cord-to-mother rate constants of 1.10 h−1 and 1.43 h−1, respectively. Placental transfer, expressed as the fetal-to-maternal area under the curve ratio, was 75%. Neonates had a very long half-lives (110 h) compared to adults. In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above the half-maximal inhibitory concentration (IC50) was 13.2 days (range, 12 to 19.2 days). Thus, the administration of tenofovir-emtricitabine for at least 3 weeks after delivery should be considered to prevent the emergence of resistant viruses. The neonate must receive sdNVP immediately after birth when the infant is born less than 30 min after maternal drug intake to keep NVP concentrations above the IC50.

Determination of total and unbound concentrations of lopinavir in plasma using liquid chromatography-tandem mass spectrometry and ultrafiltration methods.

Lopinavir is an HIV protease inhibitor with high protein binding (98-99%) in human plasma. This study was designed to develop an ultrafiltration method to measure the unbound concentrations of lopinavir overcoming the non-specific binding issue. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of total concentrations of lopinavir in plasma was developed and validated, and an adaptation was also optimized and validated for the determination of unbound concentrations. The chromatographic separation was performed with a C18 column (100 mm × 2.1mm i.d., 5 μm particle size) using a mobile phase containing deionized water with formic acid, and acetonitrile, with gradient elution at a flow-rate of 350 μL min(-1). Identification of the compounds was performed by multiple reaction monitoring, using electrospray ionization in positive ion mode. The method was validated over a clinical range of 0.01-1 μg/mL for human plasma ultrafiltrate and 0.1-15 μg/mL in human plasma. The inter and intra-assay accuracies and precisions were between 0.23% and 11.37% for total lopinavir concentrations, and between 3.50% and 13.30% for plasma ultrafiltrate (unbound concentration). The ultrafiltration method described allows an accurate separation of the unbound fraction of lopinavir, circumscribing the loss of drug by nonspecific binding (NSB), and the validated LC-MS/MS methodology proposed is suitable for the determination of total and unbound concentrations of lopinavir in clinical practice.

Determination of optimal cholecalciferol treatment in renal transplant recipients using a population pharmacokinetic approach

PurposeNo information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30–80xa0ng/mL during the first year post-transplantation.MethodsFour months after renal transplantation, 49 patients received four oral doses of 100,000xa0IU cholecalciferol every 2xa0weeks (intensive phase), then every 2xa0months until 1xa0year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment-model with first-order formation and elimination and basal concentration.ResultsThe mean population parameter estimates and the associated between-subject variability were: formation rate constant (kf), 0.11 day−1; clearance (CL/F), 2.5xa0L/day (0.42); central volume of distribution (VC/F), 237xa0L; basal concentration (C0),12.82xa0ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80xa0ng/mL, cholecalciferol dosing should be six successive administrations of 100,000xa0IU at 2-week intervals, followed by 100,000xa0IU once a month until the end of the first year.ConclusionsWe present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients.

Challenges regarding analysis of unbound fraction of highly bound protein antiretroviral drugs in several biological matrices: lack of harmonisation and guidelines

The unbound drug concentration in plasma is usually considered the only active fraction; thus the binding of a drug to a protein limits its pharmacological actions. This is of special importance for those highly bound drugs. Therefore, binding studies can be of great utility for those drugs where relationship between free and total drug concentration is variable among patients, or it can be altered by some condition or disease, or even by interactions with other drugs. However, there is a lack of validation guidelines for the determination of unbound concentrations. Antiretroviral drugs (ARVs), protease inhibitors (PIs), efavirenz and nevirapine are highly bound to proteins. Here, we present a review on the overall methods for the study of unbound fractions of highly bound plasma protein ARVs. We also provide a critical evaluation of the methods applied, their differences and the main points to be controlled and validated.

Evaluation of nevirapine dosing recommendations in HIV-infected children.

AIMSnNevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used for chronic human immunodeficiency virus infections in adults and children. The aims of this study were to investigate the population pharmacokinetics of NVP in children, establish factors that influence NVP pharmacokinetics and evaluate the current dosing recommendations.nnnMETHODSnConcentrations were measured on a routine basis in 94 children aged from 2 months to 17 years. A total of 390 NVP plasma concentrations were retrospectively collected, and a population pharmacokinetic model was developed with Monolixu20094.0.nnnRESULTSnNevirapine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. After standardization to a 70u2009kg adult using allometry, postmenstrual age had a significant effect on the bioavailability. Estimates of apparent clearance and volume of distribution were 3.9u2009lu2009h(-1) (70u2009kg)(-1) and 140u2009l (70u2009kg)(-1) , respectively. Based on simulations of European Medicines Agency (EMA) and World Health Organization (WHO) dosing recommendations, the probability of observing minimal concentrations below the efficacy target of 3u2009mgu2009l(-1) is higher following the EMA recommendations than the WHO recommendations. However, NVP underdosing persists for the 3-6 and 6-10u2009kg weight ranges following the WHO recommendations.nnnCONCLUSIONSnIt is suggested to increase doses to 75 and 100u2009mg twice daily for the 3-6 and 6-10u2009kg weight ranges, respectively, in order to obtain more than 95% of children with concentrations above 3u2009mgu2009l(-1) .

Determination of optimal vitamin D3 dosing regimens in HIV-infected paediatric patients using a population pharmacokinetic approach

AIMSnTo investigate 25-hydroxycholecalciferol [25(OH)D] population pharmacokinetics in children and adolescents, to establish factors that influence 25(OH)D pharmacokinetics and to assess different vitamin D3 dosing schemes to reach sufficient 25(OH)D concentrations (>30u2009ngu2009ml(-1) ).nnnMETHODSnThis monocentric prospective study included 91 young HIV-infected patients aged 3 to 24 years. Patients received a 100u2009000 IU vitamin D3 supplementation. A total of 171 25(OH)D concentrations were used to perform a population pharmacokinetic analysis.nnnRESULTSnAt baseline 28% of patients had 25(OH)D concentrations below 10u2009ngu2009ml(-1) , 69% between 10 and 30u2009ngu2009ml(-1) and 3% above 30u2009ngu2009ml(-1) . 25(OH)D pharmacokinetics were best described by a one compartment model with an additional production parameter reflecting the input from diet and sun exposure. The effects of skin phototype and bodyweight were significant on 25(OH)D production before any supplementation. The basal level was 27% lower in non-white skin phototype patients and was slightly decreased with bodyweight. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs. To obtain concentrations between 30 and 80u2009ngu2009ml(-1) , patients with baseline concentrations between 10 and 30u2009ngu2009ml(-1) should receive 100u2009000 IU per 3 months. However, vitamin D deficient patients (<10u2009ngu2009ml(-1) ) would need an intensive phase of 100u2009000 IU per 2 weeks (two times) followed 2 weeks later by a maintenance phase of 100u2009000 IU per 3 months.nnnCONCLUSIONSnSkin phototype and bodyweight had an influence on the basal production of 25(OH)D. According to 25(OH)D baseline concentrations, dosing schemes to reach sufficient concentrations are proposed.

Evaluation of effect of impaired renal function on lamivudine pharmacokinetics

AIMSnThis study aimed to describe lamivudine pharmacokinetics in patients with impaired renal function and to evaluate the consistency of current dosing recommendations.nnnMETHODSnA total of 244 patients, ranging in age from 18 to 79 years (median 40 years) and in bodyweight from 38 to 117u2009kg (median 71u2009kg), with 344 lamivudine plasma concentrations, were analysed using a population pharmacokinetic analysis. Serum creatinine clearance (CLCR) was calculated using the Cockcroft-Gault formula; 177 patients had normal renal function (CLCR > 90u2009mlu2009min(-1) ), 50 patients had mild renal impairment (CLCR = 60-90u2009mlu2009min(-1) ), 20 patients had moderate renal impairment (CLCR = 30-60u2009mlu2009min(-1) ), and five patients had severe renal impairment (CLCR < 30u2009mlu2009min(-1) ).nnnRESULTSnA two-compartment model adequately described the data. Typical population estimates (percentage interindividual variability) of the apparent clearance (CL/F), central (Vc /F) and peripheral volumes of distribution (Vp /F), intercompartmental clearance (Q/F) and absorption rate constant (Ka ) were 29.7u2009lu2009h(-1) (32%), 68.2u2009l, 114u2009l, 10.1u2009lu2009h(-1) (85%) and 1u2009h(-1) , respectively. Clearance increased significantly and gradually with CLCR. Our simulations showed that a dose of 300u2009mg day(-1) in patients with mild renal impairment could overexpose them. A dose of 200u2009mg day(-1) maintained an exposure close to that of adults with normal renal function. However, the current US Food and Drug Administration recommendations for lamivudine in other categories of patients (from severe to moderate renal impairment) provided optimal exposures.nnnCONCLUSIONSnLamivudine elimination clearance is related to renal function. To provide optimal exposure, patients with mild renal impairment should receive 200u2009mg day(-1) instead of 300u2009mg day(-1) .

Population Pharmacokinetic Model to Optimize Cefotaxime Dosing Regimen in Critically Ill Children

BackgroundDuring sepsis, optimal plasma antibiotic concentrations are mandatory. Modifications of pharmacokinetic parameters could lead to low drug concentrations and therefore, insufficient therapeutic levels.ObjectiveThe aim of this study was to build a population pharmacokinetic model for cefotaxime and its metabolite desacetylcefotaxime in order to optimize individual dosing regimens for critically ill children.MethodsAll children aged <xa018xa0years, weighing more than 2.5xa0kg, and receiving intermittent cefotaxime infusions were included in this study. Cefotaxime and desacetylcefotaxime were quantified by high-performance liquid chromatography. Pharmacokinetics were described using the non-linear mixed-effect modeling software MONOLIX, and Monte Carlo simulations were used to optimize dosing regimen in order to maintain serum concentrations above the target concentration (defined at 2xa0mg·L−1) throughout the dosing interval.ResultsWe included 49 children with a median (range) postnatal age of 23.7 (0.2–229)xa0months, and median body weight (range) of 10.9 (2.5–68)xa0kg. A one-compartment model with first-order elimination adequately described the data. Median (range) values for cefotaxime clearance, desacetylcefotaxime clearance, and volume of distribution were 0.97 (0.3–7.1)xa0L·h−1, 3.2 (0.6–16.3)xa0L·h−1, and 0.3 (0.2–0.41)xa0L·kg−1, respectively. Body weight and postnatal age were statistically significant covariates. Cefotaxime-calculated residual concentrations were low, and no patient succeeded in attaining the target. Unlike intermittent administration, a dosing regimen of 100xa0mg·kg−1·day−1 administered by continuous infusion provided a probability of target attainment of 100%, regardless of age and weight.ConclusionsStandard intermittent cefotaxime dosing regimens in critically ill children are not adequate to reach the target. We showed that, for the same daily dose, continuous infusion was the only administration that enabled the target to be attained, for children over 1 month of age. As continuous administration is achievable in the pediatric intensive care unit, it should be considered for clinical practice.Trial registration numberRegistered at http://www.clinicaltrials.gov, NCT02539407.

Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children with Normal and Augmented Renal Clearance

BackgroundCritically ill children frequently display observed alterations of pharmacokinetic (PK) parameters, leading to a reduction in β-lactam concentrations. This study aimed to develop a PK population model for piperacillin in order to optimize individual dosing regimens.MethodsAll children agedu2009≤u200918xa0years, weighing more than 2.5xa0kg, and receiving piperacillin infusions were included in this study. Piperacillin was quantified by high-performance liquid chromatography, and PK were described using the non-linear mixed-effect modeling software MONOLIX. Monte Carlo simulations were used to optimize dosing regimens in order to attain two PK targets: 50% fT>MIC and 100% fT>MIC.ResultsWe included 50 children with a median (range) postnatal age of 2.3xa0years (0.1–18), body weight (BW) of 11.9xa0kg (2.7–50), Pediatric Logistic Organ Dysfunction-2 (PELOD-2) severity score of 4 (0–16), and estimated glomerular filtration rate (eGFR) of 142xa0mL.min−1.1.73xa0m−2 (29–675). A one-compartment model with first-order elimination adequately described the data. Median (range) values for piperacillin clearance (CL) and volume of distribution were 3xa0L.h−1 (0.71–10) and 0.33xa0L.kg−1 (0.21–0.86), respectively. BW was integrated with the allometric relationship. eGFR and PELOD-2 severity score were the covariates explaining between-subject variability in CL and volume, respectively. According to the simulations, extended and continuous infusion provided the highest probability of reaching the target of 50% fT>MIC and 100% fT>MIC for normal and augmented renal clearance, respectively.ConclusionsUnlike standard intermittent piperacillin dosing regimens, extended and continuous infusion allows the PK targets to be reached, for children with normal or augmented renal clearance.Trial Registration NumberRegistered at http://www.clinicaltrials.gov (NCT02539407).