Summary
VRC‐HIVMAB060‐00‐AB (VRC01) is a broadly neutralizing HIV‐1 monoclonal antibody (mAb) isolated from the B cells of an HIV‐infected patient. It is directed against the HIV‐1 CD4 binding site ...and is capable of potently neutralizing the majority of diverse HIV‐1 strains. This Phase I dose‐escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose‐limiting toxicities. Mean 28‐day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28‐day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5–40 mg/kg i.v. dose range (n = 18), the clearance was 0·016 l/h and terminal half‐life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti‐VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half‐life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV‐1 prevention efficacy studies.
Clindamycin is commonly prescribed to treat children with skin and skin‐structure infections (including those caused by community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA)), yet ...little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA‐MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one‐compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)0.75 × (PMA3.1/(43.63.1 + PMA3.1)); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age‐based dosing.
Clinical Pharmacology & Therapeutics (2014); 96 4, 429–437. doi:10.1038/clpt.2014.134
Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients ...required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time‐to‐treatment with N‐acetylcysteine (NAC), and risk determination per the Rumack–Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (ke), elimination half‐lives (t1/2), and maximum concentration of adducts (Cmax) of the subjects. The mean (±SD)ke and half‐life were 0.486 ± 0.084 days-1 and 1.47± 0.30 days, respectively, and the Cmax was 1.2 (±2.92) nmol/ml serum. The model‐derived, predicted adduct value at 48 h (Adduct 48) correlated with adductCmax, adduct Tmax, Rumack–Matthews risk determination, peak aspartate aminotransferase (AST), and peak alanine aminotransferase (ALT). The pharmacokinetics and clinical correlates of APAP adducts in pediatric and adolescent patients with APAP overdose support the need for a further examination of the role of APAP adducts as clinically relevant and specific biomarkers of APAP toxicity.
Clinical Pharmacology & Therapeutics (2008); 84, 6, 684–690 doi:10.1038/clpt.2008.190
Objectives
Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy ...pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum.
Methods
International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV‐infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady‐state 24‐hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography−mass spectrometry (LC‐MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 μg h/mL (nonpregnant historical control 10th percentile).
Results
The median tenofovir AUC was decreased during the second (1.9 μg h/mL) and third (2.4 μg h/mL; P = 0.005) trimesters versus postpartum (3.0 μg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women 73%; 95% confidence interval (CI) 56%, 86% in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third‐trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third‐trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected.
Conclusions
This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV‐infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.
Candida infections are common and often fatal in infants and neonates. Anidulafungin has excellent activity against Candida species, but the pharmacokinetics (PK) and safety of the drug in infants ...and neonates are unknown. The object of our study was to determine the PK and safety of anidulafungin in infants and neonates at risk for invasive candidiasis. Intravenous anidulafungin (1.5 mg/kg/day maintenance dose) was administered to 15 infants and neonates over 3 to 5 days. Plasma samples were collected after the first dose and again after the third to fifth doses. The pharmacokinetic parameters of the drug were determined by noncompartmental analysis. Safety was assessed using National Cancer Institute common toxicity criteria. The study showed that drug exposure levels were similar between neonates and infants; the median areas under the concentration–time curve (range) was 75 (30–109) µg·h/ml and 98 (55–278) µg·h/ml (P = 0.12) for neonates and infants, respectively. No drug‐related serious adverse events were observed. The study results indicate that neonates and infants receiving 1.5 mg/kg/day have anidulafungin exposure levels similar to those in children receiving similar weight‐based dosing and in adult patients receiving 100 mg/day.
Clinical Pharmacology & Therapeutics (2011) 89 5, 702–707. doi:10.1038/clpt.2011.26
Improved antiretroviral therapies are needed for the treatment of HIV‐infected infants, given the rapid progression of the disease and drug resistance resulting from perinatal exposure to ...antiretrovirals. We examined longitudinal pharmacokinetics (PK) data from a clinical trial of lopinavir/ritonavir (LPV/r) in HIV‐infected infants in whom therapy was initiated at less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LPV) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only covariates found to be significant. Population PK of LPV was characterized by high apparent clearance (CL/F) in young infants, which decreased with increasing age. Although younger infants had lower LPV concentrations, the viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band–based dosing recommendations predicted therapeutic LPV concentrations and provided drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)‐suggested dosing regimens.
Clinical Pharmacology & Therapeutics (2012); 91 2, 243–249. doi:10.1038/clpt.2011.218
Objectives
Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6‐β hydroxycortisol to cortisol (6βHF : ...F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)‐treated HIV‐1‐infected women and to relate this change to ARV pharmacokinetics.
Methods
Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (> 30 weeks) and postpartum with determination of 6βHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau.
Results
6βHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P = 0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6βHF : F comparison was marginally significant (P = 0.058). When the change in the 6βHF : F ratio was related to the change in the dose‐adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P = 0.125), albeit this correlation did not reach statistical significance.
Conclusions
A 35% increase in the urinary 6βHF : F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6βHF : F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy.
A vancomycin population pharmacokinetic prediction model for adult and elderly patients was developed using NONMEM. The predictability of the model was studied and compared with ten other models.
...Data were collected from routine care of 141 subjects. NONMEM was used to derive a population model. After internal evaluation using the bootstrap technique, external validation was studied using an independent dataset that consisted of 95 subjects; a statistical comparison of precision and bias was conducted.
A two-compartment open model was derived with body weight, age, and CLcr as covariates. The bootstrap process showed stability of the model. A comparison of subjects older and younger than 65 years found that the older group had a mean clearance of 2.24 (+/- 1.2) l/h compared to 4.03 (+/- 1.7) l/h, and a peripheral volume of 43.7 (+/- 5.1) l compared to 28.4 (+/- 5.3) l compared to younger patients. These values were modeled using CLcr in the clearance equation and Vd as a function of age. The eleven models studied showed a bias in predicting serum concentrations from the test database that ranged from 0.35 mg/l to -5.93 mg/l. Precision ranged from 4.53 mg/l to 8.05 mg/l. Our method ranked in fourth place overall and when compared statistically its bias was different from the method that ranked in second place by -1.45 (95% CI -2.46, -0.42; p = 0.005), and different from all the methods that ranked worse. The only difference in precision was with the method that ranked in eleventh place with a relative precision of 0.49 (95% CI 0.27, 0.70; p < 0.001).
A two-compartment open model fitted the data with weight, age, and CLcr as covariates. The derived method ranked in fourth place overall. The two-compartment nature of two of the equations studied did not provide an advantage. A future study with more data in the distribution phase could provide a model with better predictability.
Background
Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and α‐1 acid glycoprotein (AAG). Small changes in PB can ...greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to ≥1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously.
Methods
P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP.
Results
AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96±0.16% AP vs. 0.82±0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG.
Conclusions
LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.
Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of pubertal children and young adults. Antiretroviral therapy (ART) in adolescents is complex and depends ...on multiple factors. The continued use of higher (weight‐ or surface‐based) pediatric doses can result in potentially toxic drug exposure, whereas early introduction of lower adult doses can lead to the development of drug resistance and virologic failure. The physiological and psychosocial changes during puberty create strong grounds for an individualized therapeutic approach in HIV‐infected adolescents.
Clinical Pharmacology & Therapeutics (2008); 84, 6, 734–740 doi:10.1038/clpt.2008.187
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