Corticosteroid treatment and mortality in mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients: a multicentre cohort study.

BACKGROUND: Some unanswered questions persist regarding the effectiveness of corticosteroids for severe coronavirus disease 2019 (COVID-19) patients. We aimed to assess the clinical effect of corticosteroids on intensive care unit (ICU) mortality among mechanically ventilated COVID-19-associated acute respiratory distress syndrome (ARDS) patients. METHODS: This was a retrospective study of prospectively collected data conducted in 70 ICUs (68 Spanish, one Andorran, one Irish), including mechanically ventilated COVID-19-associated ARDS patients admitted between February 6 and September 20, 2020. Individuals who received corticosteroids for refractory shock were excluded. Patients exposed to corticosteroids at admission were matched with patients without corticosteroids through propensity score matching. Primary outcome was all-cause ICU mortality. Secondary outcomes were to compare in-hospital mortality, ventilator-free days at 28 days, respiratory superinfection and length of stay between patients with corticosteroids and those without corticosteroids. We performed survival analysis accounting for competing risks and subgroup sensitivity analysis. RESULTS: We included 1835 mechanically ventilated COVID-19-associated ARDS, of whom 1117 (60.9%) received corticosteroids. After propensity score matching, ICU mortality did not differ between patients treated with corticosteroids and untreated patients (33.8% vs. 30.9%; p = 0.28). In survival analysis, corticosteroid treatment at ICU admission was associated with short-term survival benefit (HR 0.53; 95% CI 0.39-0.72), although beyond the 17th day of admission, this effect switched and there was an increased ICU mortality (long-term HR 1.68; 95% CI 1.16-2.45). The sensitivity analysis reinforced the results. Subgroups of age < 60 years, severe ARDS and corticosteroids plus tocilizumab could have greatest benefit from corticosteroids as short-term decreased ICU mortality without long-term negative effects were observed. Larger length of stay was observed with corticosteroids among non-survivors both in the ICU and in hospital. There were no significant differences for the remaining secondary outcomes. CONCLUSIONS: Our results suggest that corticosteroid treatment for mechanically ventilated COVID-19-associated ARDS had a biphasic time-dependent effect on ICU mortality. Specific subgroups showed clear effect on improving survival with corticosteroid use. Therefore, further research is required to identify treatment-responsive subgroups among the mechanically ventilated COVID-19-associated ARDS patients.

A population pharmacokinetic model taking into account protein binding for the sustained-release granule formulation of valproic acid in children with epilepsy.

PURPOSE: The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (Ctrough) within the target range (50-100 mg/L). METHODS: Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain Ctrough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg. RESULTS: A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a Ctrough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%. CONCLUSIONS: If the present study supports the current dose recommendations of 20-30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.

Population Pharmacokinetics of Stiripentol in Paediatric Patients with Dravet Syndrome Treated with Stiripentol, Valproate and Clobazam Combination Therapy.

AIM: The aim of this study was to describe the pharmacokinetics of stiripentol in children with Dravet syndrome and to determine the concentrations of stiripentol achieved in this population for the usual 25 mg/kg twice-daily dose. METHODS: Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using MONOLIX software). Four blood samples were drawn per patient. Stiripentol area under the plasma concentration-time curve (AUC) values and trough concentrations were simulated for 7000 theoretical children weighing between 10 and 70 kg for the 25 mg/kg twice-daily dose. RESULTS: The pharmacokinetics of stiripentol was described using a one-compartment model with zero-order absorption and first-order elimination. The apparent clearance (CL/F) and apparent volume of distribution (V d/F) of stiripentol were related to body weight by allometric equations. A dose-dependent non-linearity was also observed with an allometric model relating CL/F to the weight-normalised dose. Mean population estimates (% inter-individual variability) were 4.2 L/h (21%) for CL/F and 82 L (25%) for V d/F. The AUC of stiripentol increased by 300% when body weight increased from 10 to 70 kg. CONCLUSION: This population pharmacokinetic model of stiripentol in children with Dravet syndrome confirmed the dose-dependent non-linearity that has been evidenced in adults. It also supported that a 25 mg/kg twice-daily dose might lead to excessive exposure in children >30 kg, suggesting an eventual dose adjustment during adolescence. CLINICAL TRIAL IDENTIFIER: This study is part of the STIPOP study (EUDRACT number: 2007-001784-30).

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.

AIMS: Oxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (Ctrough ) of MHD (3-35 mg l-1 ). METHODS: A total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain Ctrough between 3-35 mg l-1 was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg-1  day-1 . RESULTS: A parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140 l h-1  70 kg-1 , 337 l 70 kg-1 , 60.7 l and 62.5 l h-1 , respectively. Typical values for MHD clearance and distribution volume were 4.11 l h-1  70 kg-1 and 54.8 l 70 kg-1 respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20-30 mg kg-1  day-1 instead of the recommended target maintenance dose (30-45 mg kg-1  day-1 ) to obtain Ctrough within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg-1  day-1 instead of the maximum recommended dose of 60 mg kg-1  day-1 . CONCLUSION: This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs.

Pharmacokinetics of clobazam and N-desmethylclobazam in children with dravet syndrome receiving concomitant stiripentol and valproic Acid.

AIM: The aim of this study was to describe the pharmacokinetics of clobazam and its active metabolite N-desmethylclobazam (N-CLB) in children with Dravet syndrome receiving the stiripentol/valproic acid/clobazam combination therapy of reference and to determine the concentrations of clobazam and N-CLB obtained in this population for the usual 0.2 mg/kg twice-daily dose. METHODS: Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using NONMEM(®) software). Four blood samples were drawn per patient. Area under the plasma concentration-time curve (AUC) and trough concentration (C trough) values for clobazam and N-CLB were simulated for 12,000 theoretical children weighing between 10 and 60 kg. RESULTS: The pharmacokinetics of clobazam were described by a one-compartment model with first-order absorption, and elimination, formation and elimination of N-CLB were also first-order processes. The apparent total clearance (CL/F) and distribution volume (V CLB/F) of clobazam and the elimination rate constant of N-CLB (Kem) were related to body weight by allometric equations. Mean population estimates (% inter-individual variability) were 1.23 L/h (29%) for CL/F, 39.1 L (18%) for V CLB/F and 0.0706 h(-1) (26%) for Kem. The AUC values for clobazam and N-CLB were found to increase by 100% when bodyweight increased from 10 to 60 kg, and the simulated C trough values were higher than the currently accepted target values (0.03-0.3 mg/L for clobazam and 0.3-3 mg/L for N-CLB). CONCLUSION: This is the first simultaneous pharmacokinetic model for clobazam and N-CLB in epileptic children. Indicative values for the routine therapeutic drug monitoring of clobazam in children with Dravet syndrome treated by stiripentol are provided. The possible consequences of the weight-related changes on clobazam and N-CLB exposures should be further evaluated.

Reassessment of stiripentol pharmacokinetics in healthy adult volunteers.

Because children who have been receiving stiripentol for the treatment of Dravet syndrome for more than 10 years are now becoming young adults, it is important to accurately characterize stiripentol pharmacokinetics in this age range. A double-blind placebo-controlled dose ranging study was therefore conducted to investigate the pharmacokinetics and tolerability of stiripentol in 12 healthy volunteers. Each subject received 3 single doses of stiripentol (500, 1000, and 2000 mg) separated by a wash-out period of 1 week. Pharmacokinetics of stiripentol was analyzed for each dose by non-compartmental analysis. Median area under the curve (AUC), terminal elimination half-life (t1/2,z) and maximal concentration (Cmax) were calculated for between-dose comparison. Safety was evaluated based on both clinical and biological criteria. Oppositely to previous results, there was no concentration rebounds in the elimination phase, which could be the consequence of the food intake. A more than proportional increase in the AUC was observed, associated with a significant increase in the t1/2,z, for increasing doses (median AUC of 8.3, 31 and 88 mgh/L, and median t1/2,z of 2, 7.7 and 10h for the 500, 1000, and 2000 mg doses respectively), which confirmed the Michaelis-Menten pharmacokinetics of Stiripentol. However, dose-normalized Cmax did not significantly vary between doses. Median Michaelis-Menten parameters were 117 mg/h for Vmax and 1.9 mg/L for Km. No safety concern was observed during the study. The present study allowed a better characterization of the disposition phase of stiripentol and confirmed its non-linear pharmacokinetic behaviour. Further pharmacokinetic/pharmacodynamic studies would be useful to determine the optimal dose of stiripentol for the treatment of Dravet patients in adulthood.

Effectiveness of liposomal amphotericin B in patients admitted to the ICU on renal replacement therapy.

INTRODUCTION: This study was designed to compare the effectiveness of liposomal amphotericin B (L-AmB) in ICU patients with and without renal replacement therapy (RRT). METHODS: Observational, retrospective, comparative and multicenter study conducted in critically ill patients treated with L-AmB for 3 or more days, divided into two cohorts depending on the use of RRT before or within the first 48 hours after starting L-AmB. Clinical and microbiological response at the end of treatment was evaluated. RESULTS: A total of 158 patients met the inclusion criteria, 36 (22.8%) of which required RRT during the ICU stay. Patients with RRT as compared with those without RRT showed a higher APACHE II score on admission (21.4 vs 18.4, P = 0.041), greater systemic response against infection (P = 0.047) and higher need of supportive techniques (P = 0.002). In both groups, main reasons for the use of L-AmB were broad spectrum and hemodynamic instability. A higher daily dose of L-AmB was used in the RRT group (4.30 vs 3.84 mg/kg, P = 0.030) without differences in the total cumulative dose or treatment duration. There were no differences in the clinical response (61.1% vs 56.6%, P = 0.953) or microbiological eradication rate (74.1% vs 64.6%, P = 0.382). In patients with proven invasive fungal infection, satisfactory clinical response was obtained in 74.1% and microbiological eradication 85.7%. CONCLUSIONS: Although the study sample is small, this study shows that L-AmB is effective in critically ill patients admitted to the ICU requiring RRT.

Pregnancy-related effects on tenofovir pharmacokinetics: a population study with 186 women.

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 (C(min)) as observed in adults, an increase in the TFV dose should be considered for women from the second trimester to delivery.

Pregnancy-related effects on lamivudine pharmacokinetics in a population study with 228 women.

The aim of this study was to describe lamivudine (3TC) pharmacokinetics (PK) in HIV-infected nonpregnant and pregnant women and their fetuses. Samples were collected according to therapeutic drug monitoring from 228 women treated with lamivudine and retrospectively analyzed by a population approach. The samples were also collected from cord blood and amniotic fluid at birth. Lamivudine pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. Mean population parameter estimates (intersubject variability) for women were an absorption rate constant of 1.04 h(-1), an elimination clearance rate of 23.6 (0.266) liters · h(-1), a central volume of distribution of 109 (0.897) liters, an intercompartmental clearance rate of 6.7 liters/h, and a peripheral volume of distribution of 129 liters. A fetal compartment was linked to maternal circulation by mother-to-cord (or fetus) and cord-to-mother rate constants of 0.463 h(-1) and 0.538 h(-1), respectively. The amniotic fluid compartment was connected to the fetal compartment with an elimination rate constant of 0.163 h(-1) and a fixed-constant swallowing flow. The placental transfer expressed as fetal-to-maternal area under the concentration-time curve (AUC) ratio was 0.86, and the lamivudine amniotic fluid accumulation, expressed as the amniotic fluid-to-fetal AUC ratio, was 2.9. Pregnant women had a 22% higher apparent clearance than nonpregnant and parturient women; however, this increase did not lead to subexposure and should not require a dosage adjustment.

Population pharmacokinetics of tenofovir in HIV-1-infected pediatric patients.

OBJECTIVES: To evaluate the pharmacokinetics of tenofovir in children and the influence of covariates [body weight (BW), age, cotreatments]. The main goal was then to suggest for the first time the dose of tenofovir disoproxil fumarate (TDF) to give in children. DESIGN/METHODS: Tenofovir concentrations were monitored on a routine basis and measured in 93 children aged 5 to 18 years; 283 tenofovir plasma concentrations were used to perform a population pharmacokinetic analysis. RESULTS: A 2-compartment model adequately described the data. A BW allometric scaling was used; and the typical population estimates (interindividual variability), standardized for 70 kg, for apparent clearance, central and peripheral volume of distribution, intercompartmental clearance, and absorption rate constant, were 59.8 L·h⁻¹ (0.48), 386 L (1.39), 666 L, 92.8 L·h⁻¹ and 0.43 h⁻¹, respectively. TDF clearance increased significantly with BW and decreased with lopinavir/ritonavir (LPV/r) coadministration, thus these factors were used to propose doses for children. Dosing scheme, according BW and LPV/r coadministration were simulated to produce the same 24-hr exposure as adults after 300-mg TDF dose. CONCLUSIONS: Children without LPV/r should receive: 150 mg TDF from 20 to 30 kg, 225 mg TDF from 30 to 40 kg, and the adult dosage of 300 mg TDF over 40 kg. To avoid risk of renal toxicity, TDF dose should be decreased when coadministrated with LPV/r, children should receive 150 mg TDF from 20 to 40 kg, 225 mg TDF from 40 to 55 kg, and the adult dosage of 300 mg TDF over 55 kg.

Developmental pharmacokinetics of lamivudine in 580 pediatric patients ranging from neonates to adolescents.

Lamivudine concentration-time courses were described for a very large range of ages to study the effects of body weight and maturation on lamivudine pharmacokinetics and to check the consistency of dosing recommendations. Lamivudine concentrations were monitored on a routine basis to produce concentrations similar to the known values in adults. Concentrations were measured in 580 children from 2 days to 18 years old. A total of 2,106 plasma lamivudine concentrations were measured, and a population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization algorithm implemented in MONOLIX 3.1 software. A two-compartment model adequately described the data. After standardization for a mean standard body weight by using an allometric model, age also had a significant effect on clearance maturation. Typical population estimates (percent interindividual variability) standardized for 70 kg of the apparent clearance, including central and peripheral volumes of distribution, intercompartmental clearance, and absorption rate constant, were 31 liters · h(-1) (32%), 76.4 liters (77%), 129 liters, 5.83 liters · h(-1), and 0.432 h(-1), respectively. According to the model, elimination clearance (liters/h/70 kg) increases gradually during the first years of life. Theoretical doses needed to reach the range of 24 h of exposure observed in adults were calculated: to be closer to adult exposure, children should receive 4 mg/kg/day from birth to 8 weeks of age, 5 mg/kg/day from 8 to 16 weeks of age, 6 mg/kg from 16 to 25 weeks of age, 8 mg/kg/day from 25 weeks of age to 14 kg of body weight, 150 mg/day from 14 to 25 kg of body weight, 225 mg/day from 25 to 35 kg of body weight, and 300 mg/day thereafter.

Topiramate pharmacokinetics in infants and young children: contribution of population analysis.

PURPOSE: To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3-9 mg/kg/day) and to compare them to adult target ranges. METHODS: The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations (C(trough)s) within the adult ranges. RESULTS: TPM pharmacokinetics was described by a one-compartment model. EIAEDs increased the apparent clearance (CL/F) and age and body weight increased the apparent distribution volume (Vd/F). Mean population estimates (% CV interindividual variability) were 0.608/1.15 L/h (13%) for CL/F without/with EIAEDs, 28.6L (0.2%) for Vd/F and 1.4h(-1) (124%) for the absorption rate constant. Mean AUC(0-12h) reached with a 2mg/kg/day dosing regimen was within described range. A 6-16 mg/kg/day dose depending on age allowed reaching target C(trough) range with the highest probability. Combined EIAEDs led to a 2- and 3-fold decrease in AUC and C(trough), respectively. CONCLUSION: TPM dosage of 2/4 mg/kg/day (without/with EIEADs, respectively) provides the AUC reported in adults. In children under 4, alternative dosing regimen should be considered mainly when associated to EIAED to reach C(trough) comparable to adult values.

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

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 (IC(50)) 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 IC(50).

Developmental pharmacokinetics of etoposide in 67 children: lack of dexamethasone effect.

PURPOSE: A randomized clinical trial examined whether dexamethasone administration prior to ondansetron followed by etoposide and carboplatin infusions, and single-nucleotide polymorphisms (SNPs) of CYP3A4, CYP3A5 and MDR1 genes could modify etoposide pharmacokinetics in pediatric patients. METHODS: Patients, 67 children, aged 14 weeks to 16.7 years, were treated for various malignancies and received either 3- or 5-day courses of etoposide and carboplatin: these two drugs were always administered after ondansetron infusion but combined or not with dexamethasone 5 mg/m²/day 30 min prior to etoposide infusion. Population pharmacokinetics was modeled using a non-linear mixed effect model program (Monolix version 31 s). RESULTS: Etoposide pharmacokinetics was ascribed to a 2-compartment model. The most significant covariate effect was bodyweight (BW), so the parameters were standardized to a 70-kg BW using the allometric ¾ or 1 power model for clearance (CL, Q) or volume terms (V), respectively. The population means for clearance and central volume of distribution were 2.05 l/h/70 kg and 9.21 l/70 kg with the corresponding between-subject variabilities, 0.26 and 0.28. Dexamethasone treatment had no effect on CL, either at the first or at the last administration occasion. CYP3A and MDR1 examined SNPs had no significant effect. CONCLUSION: Pharmacokinetics of etoposide was influenced by BW on an allometric basis in this pediatric population. Dexamethasone did not influence etoposide pharmacokinetics during these 3-5 days courses. These results should allow a better individualization of etoposide dosing in children.

Intracellular Pharmacokinetics of Antiretroviral Drugs in HIV-Infected Patients, and their Correlation with Drug Action.

In patients infected by HIV, the efficacy of highly active antiretroviral (ARV) therapy through the blockade of different steps of the retrovirus life cycle is now well established. As HIV is a retrovirus that replicates within the cells of the immune system, intracellular drug concentrations are important to determine ARV drug efficacy and toxicity. Indeed, nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), newly available integrase inhibitors and protease inhibitors (PIs) act on intracellular targets. NRTIs are prodrugs that require intracellular anabolic phosphorylation to be converted into their active form of triphosphorylated NRTI metabolites, most of which have longer plasma half-lives than their parent compounds. The activity of intracellular kinases and the expression of uptake transporters, which may depend on cell functionality or their activation state, may greatly influence intracellular concentrations of triphosphorylated NRTI metabolites. In contrast, NNRTIs and PIs are not prodrugs, and they exert their activity by inhibiting enzyme targets directly. All PIs are substrates of cytochrome P450 3A, which explains why most of them display poor pharmacokinetic properties with intensive presystemic first-pass metabolism and short elimination half-lives. There is evidence that intracellular concentrations of PIs depend on P-glycoprotein and/or the activity of other efflux transporters, which is modulated by genetic polymorphism and coadministration of drugs with inhibiting or inducing properties. Adequate assay of the intracellular concentrations of ARVs is still a major technical challenge, together with the isolation and counting of peripheral blood mononuclear cells (PBMCs). Furthermore, intracellular drug could be bound to cell membranes or proteins; the amount of intracellular ARV available for ARV effectiveness is never measured, which is a limitation of all published studies. In this review, we summarize the findings of 31 studies that provided results of intracellular concentrations of ARVs in HIV-infected patients. Most studies also measured plasma concentrations, but few of them studied the relationship between plasma and intracellular concentrations. For NRTIs, most studies could not establish a significant relationship between plasma and triphosphate concentrations. Only eight published studies reported an analysis of the relationships between intracellular concentrations and the virological or immunological efficacy of ARVs in HIV patients. In prospective studies that were well designed and had a reasonable number of patients, virological efficacy was found to correlate significantly with intracellular concentrations of NRTIs but not with plasma concentrations. For PIs, the only prospectively designed trial of lopinavir found that virological efficacy was influenced by both trough plasma concentrations and intracellular concentrations. ARVs are known to cause important adverse effects through interference with cellular endogenous processes. The relationship between intracellular concentrations of ARVs and their related toxicity was investigated in only four studies. For zidovudine, the relative strength of the association between a decrease in haemoglobin levels and plasma zidovudine concentrations, as compared with intracellular zidovudine triphosphate concentrations, is still unknown. Similarly, for efavirenz and neuropsychological disorders, methodological differences confound the comparison between studies. In conclusion, intracellular concentrations of ARVs play a major role in their efficacy and toxicity, and are influenced by numerous factors. However, the number of published clinical studies in this area is limited; most studies have been small and not always adequately designed. In addition, standardization of assays and PBMC counts are warranted. Larger and prospectively designed clinical studies are needed to further investigate the links between intracellular concentrations of ARVs and clinical endpoints.

Functional role of p-glycoprotein and binding protein effect on the placental transfer of lopinavir/ritonavir in the ex vivo human perfusion model.

Aims. To study the influence of P-glycoprotein (P-glycoprotein, ABCB1, MDR1) function on placental transfer of lopinavir with ritonavir at different albumin concentrations. Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases. Results. In the control phase, the clearance index of lopinavir decreased from 0.401 +/- 0.058 to 0.007 +/- 0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95% of CI difference [-0.156, -0.002], P = .046) and became positive for ritonavir. Conclusions. Even at high albumin concentrations, inhibition of placental P-glycoprotein increased placental transfer of lopinavir, suggesting that this efflux pump actively reduces placental transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy.

Benefit of therapeutic drug monitoring of protease inhibitors in HIV-infected patients depends on PI used in HAART regimen--ANRS 111 trial.

As a result of high inter-patient variability, and efficacy-concentration and toxicity-concentration relationships, optimization of HIV-protease inhibitor (PI) doses based on plasma concentrations could be beneficial. During a 48-week open prospective non-randomized interventional study of 115 protease inhibitor-naïve patients initiating an indinavir/ritonavir- or lopinavir/ritonavir-, or nelfinavir-containing therapy, protease inhibitor dose was modified when plasma trough concentrations (C(trough)) at weeks 2, 8, 16 and 24 were outside predefined optimal concentration ranges. Failure of the strategy was defined as the proportions of patients with HIV-RNA above 200 copies/mL from weeks 24 to 48 and/or experiencing grades 2, 3 or 4 PI-related adverse events during the study; proportion of patients with last C(trough) measurement outside the concentration range was determined at each visit. Virological failure and/or occurrence of adverse event were observed in 37/94 assessable patients (39%; 95% CI: 29.4-50.0). In the on-treatment analysis, failure of the strategy was noted in 16% of indinavir/r- or lopinavir/r-treated patients (8/51; 95% CI: 7.0-28.6; virological failure: 2; adverse event: 6) but in 44% of nelfinavir-treated patients (11/25; 95% CI: 24.4-65.1; virological failure: 10; adverse event: 1); C(trough) concentrations outside the range were less frequent at the last measurement than at W2 (41% vs. 66%; P < 0.05), with proportions of 35% for indinavir/r- or lopinavir/r-treated patients, but 57% for nelfinavir-treated patients. The proposed strategy of therapeutic drug monitoring may be beneficial to indinavir/r- and lopinavir/r-treated patients, but failed to move concentrations into the predefined range and to produce the expected virological success for nelfinavir-treated patients.

High frequency of antiretroviral drug resistance among HIV-infected adults receiving first-line highly active antiretroviral therapy in N'Djamena, Chad.

Antiretroviral drug resistance was evaluated in 88 adults infected with human immunodeficiency virus, most with subtype CRF11_cpx, who had received a first-line antiretroviral regimen for 6 months, in N'Djamena, Chad. A total of 47 patients (53%) had detectable viral load at month 6, and 56 (64%) had at least 1 antiretroviral resistance mutation observed.

Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART.

AIMS: To assess the relationship between genetic polymorphisms and indinavir pharmacokinetic variability and to study the link between concentrations and short-term response or metabolic safety. METHODS: Forty protease inhibitor-naive patients initiating highly active antiretroviral therapy (HAART) including indinavir/ritonavir and enrolled in the COPHAR 2-ANRS 111 trial were studied. At week 2, four blood samples were taken before and up to 6 h following drug intake. A population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization (SAEM) algorithm implemented in MONOLIX software. The area under the concentration-time curve (AUC) and maximum (C(max)) and trough concentrations (C(trough)) of indinavir were derived from the population model and tested for their correlation with short-term viral response and safety measurements, while for ritonavir, these same three parameters were tested for their correlation with short-term biochemical safety RESULTS: A one-compartment model with first-order absorption and elimination best described both indinavir and ritonavir concentrations. For indinavir, the estimated clearance and volume of distribution were 22.2 L/h and 97.3 L, respectively. The eight patients with the *1B/*1B genotype for the CYP3A4 gene showed a 70% decrease in absorption compared to those with the *1A/*1B or *1A/*1A genotypes (0.5 vs. 2.1, P = 0.04, likelihood ratio test by permutation). The indinavir AUC and C(trough) were positively correlated with the decrease in human immunodeficiency virus RNA between week 0 and week 2 (r = 0.4, P = 0.03 and r = -0.4, P = 0.03, respectively). Patients with the *1B/*1B genotype also had a significantly lower indinavir C(max) (median 3.6, range 2.1-5.2 ng/mL) than those with the *1A/*1B or *1A/*1A genotypes (median 4.4, range 2.2-8.3 ng/mL) (P = 0.04) and a lower increase in triglycerides during the first 4 weeks of treatment (median 0.1, range -0.7 to 1.4 vs. median 0.6, range -0.5 to 1.7 mmol/L, respectively; P = 0.02). For ritonavir, the estimated clearance and volume of distribution were 8.3 L/h and 60.7 L, respectively, and concentrations were not found to be correlated to biochemical safety. Indinavir and ritonavir absorption rate constants were found to be correlated, as well as their apparent volumes of distribution and clearances, indicating correlated bioavailability of the two drugs. CONCLUSION: The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir.

Evaluation of cefotaxime and desacetylcefotaxime concentrations in cord blood after intrapartum prophylaxis with cefotaxime.

Preterm premature rupture of the membranes is associated with a high risk of neonatal sepsis. An increase in the incidence of early-onset neonatal sepsis due to ampicillin-resistant Escherichia coli in premature infants has been observed in the past few years. Intrapartum prophylaxis with ampicillin has proven to be efficient for the prevention of early neonatal sepsis due to group B streptococci. To date, there is no strategy for the prevention of early neonatal sepsis due to ampicillin-resistant E. coli. Our aim was to investigate whether a standardized dosage regimen of intrapartum cefotaxime could provide concentrations in the cord blood greater than the cefotaxime MIC(90) for E. coli. Seven pregnant women hospitalized with preterm premature rupture of the membranes and colonized with ampicillin-resistant isolates of the family Enterobacteriaceae were included. Cefotaxime was given intravenously during delivery, as follows: 2 g at the onset of labor and then 1 g every 4 h until delivery. Blood specimens were collected from the mother 30 min after the first injection and just before the second injection, and at birth, blood specimens were simultaneously collected from the mother and the umbilical cord. The concentrations of cefotaxime in the cord blood ranged from 0.5 to 8.5 mg/liter. The MIC(90) of cefotaxime for E. coli strains (0.125 mg/liter) was achieved in all cases. This preliminary study supports the use of cefotaxime for intrapartum prophylaxis in women colonized with ampicillin-resistant isolates of Enterobacteriaceae. The effectiveness of this regimen for the prevention of neonatal sepsis needs to be evaluated with a larger population.