The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n ‫؍‬ 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue used as a component of combination therapy with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. All nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) require intracellular conversion to the triphosphate anabolite, which inhibits the viral reverse transcriptase. Unlike nucleosides that require sequential phosphorylation to the mono-, di-, and finally triphosphate for activation, nucleotides such as tenofovir (TFV) require only two such steps because they are monophosphate analogs and do not require the initial phosphorylation reaction. Conventionally, the triphosphate anabolite of TFV is referred to as tenofovir diphosphate (TFV-DP) because only two phosphate groups are added. As the initial phosphorylation step is potentially a limiting factor in the activation of NRTIs in resting CD4 ϩ cells and macrophages, TFV may result in better antiviral activity than other NRTIs in cells that have limited proliferative and phosphorylative capacities. Since TFV is activated to TFV-DP in both active and resting cells (20), it has the property of inhibiting HIV replication in macrophages and other nondividing cells not found uniformly among the NRTI class (14).A central feature of the clinical pharmacology of NRTIs is the dependence of virologic response upon the pharmacokinetics of the intracellular triphosphate anabolite. The lack of knowledge of intracellular NRTI-triphosphate pharmacokinetics contributed to the initial use of higher doses and more frequent dosing and the eventual dose de-escalation of early NRTIs such as didanosine, stavudine, and zidovudine. The lack of knowledge of relationships between extracellular concentrations of the NRTIs and intracellular amounts of their active metabolites remains a significant gap in our knowledge of these agents and limits our ability to fully understand exposure-response relationships and use that information to predict responses to alternative dosing regimens, concomitant disease states, and other drugs. The objective of the present work was to develop a model to characterize the plasma and intracellular p...

A population pharmacokinetic analysis of cyclosporine (CsA) was performed, and the influence of covariates on CsA oral clearance and relative bioavailability was investigated. Data from 48 recipients of heart-lung (n = 21) or single (n = 18) or double (n = 9) lung transplant were included in the study. Patients received oral CsA as either a conventional formulation (Sandimmune) or a microemulsion (Neoral). Steady-state CsA concentrations were measured before and at approximately 2 and 6 hours after the morning dose of CsA at the end of weeks 1, 2, 3, 4, 13, 26, 39, and 52 posttransplantation. A total of 1004 CsA concentration observations were analyzed using mixed effects-modeling (NONMEM). A 1-compartment pharmacokinetic model and first-order oral absorption were used to fit the data. The absorption rate constants were fixed at 0.25 L/h for Sandimmune and 1.35 L/h for Neoral formulations. Oral clearance (CL/F) was estimated to be 22.1 L/h (95% confidence intervals [CI] 19.5-24.7 L/h). Itraconazole (ITRA), cystic fibrosis (CF), and weight (WT) were identified as significant covariates for CL/F according to the final model: CL/F = 22.1 - 11.3 x ITRA + 23.5 x CF + 0.129 x (WT - 58.7) L/h; where ITRA = 1 if the patient was taking concomitant itraconazole, otherwise 0; CF = 1 if the patient had cystic fibrosis, otherwise CF = 0; and WT is patient weight in kilograms. The relative oral bioavailability of Sandimmune to Neoral was 0.82. The bioavailability of both preparations increased during the first month posttransplantation. Age, gender, and type of transplant (single, double, or heart-lung) were not identified as significant covariates for CsA clearance. The population pharmacokinetic model developed identified some sources of variability in CsA pharmacokinetics; however, an appreciable degree of variability is still present in this patient population.

Introduction There is limited pediatric information on the complex relationships among the dose of tenofovir disoproxil fumarate (TDF), plasma concentrations of tenofovir (TFV), and intracellular TFV-diphosphate (TFV-DP) concentrations. Our objectives were to describe TFV-DP pharmacokinetics in children and adolescents and investigate the effect of age on TFV and TFV-DP concentrations. Methods TFV-DP pharmacokinetics were determined in 47 children and adolescents. TFV and TFV-DP were quantified with validated LC/MS/MS methods. Data were pooled with other studies in HIV-infected adults (N=55). Nonlinear mixed effects modeling was used to develop the population model and explore the influence of covariates on TFV. A two-compartment model, partitioned for slow and fast absorbers by age, with weight allometrically scaled for children and adolescents best described TFV pharmacokinetics. An indirect stimulation of response model best described TFV-DP formation. Results Apparent oral TFV clearance (CL/F) was significantly faster in patients <25 versus ≥25 years. The most significant covariate on CL/F and central distribution volume was creatinine clearance. The TFV plasma concentration producing 50% of maximal TFV-DP concentrations (EC50) was almost 2-fold lower in patients <25 versus ≥25 years. The estimated intracellular TFV-DP half-life for these groups was 70 and 87 hours, respectively. Conclusions These data demonstrate children and adolescents receiving standard TDF dosing of 300 mg once daily achieve higher intracellular TFV-DP concentrations than adults, despite lower plasma TFV concentrations. This age-related difference appears to arise from an increased sensitivity to formation of TFV-DP.

Purpose: Immunoglobulin (Ig) G replacement therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is the standard treatment in patients with primary immunodeficiencies (PID). We aimed to characterize the pharmacokinetic (PK) characteristics of serum IgG following administration of IgPro10 every 3 or 4 weeks in Japanese patients with PID, and compare with PK in non-Japanese patients. A previously developed population PK (PPK) model was validated, and predicted parameters were compared with the results from the clinical study. Methods: The previously developed PPK model, containing IgG concentration data from 5 non-Japanese studies, was supplemented with data from 3 Japanese studies of IgPro10 or IgPro20 to compare the IgG PK parameters between Japanese and non-Japanese patients. The model was externally validated by simulating IgG concentrationetime profiles in Japanese patients to predict serum IgG PK characteristics and to compare them with observed Japanese PK data from Study IgPro10_3004. Findings: The analysis included 4502 serum IgG concentration values (from 34 Japanese and 168 non-Japanese patients). PPK estimates from the current analysis demonstrated a clearance (CL) of 0.139 L/d, central volume (V2) of 4.01 L, inter-compartmental clearance (Q) of 0.30 L/d, and peripheral volume of 3.51 L. These results were consistent with those from the previously published PPK model, with similar bootstrap means and 95% CIs. Goodness-of-fit criteria indicated that the final PPK model was consistent with observed data, with no systemic bias in model prediction. Prediction-corrected visual predictive checks confirmed a good description of data on both SCIG and IVIG. PK parameters were equivalent between Japanese and non-Japanese patients. Body weight was determined to be a significant covariate on both CL and V2. Simulated and observed AUC and maximum and minimum serum IgG concentrations were similar, with 90% CIs overlapping between simulated and observed IgG concentrations in Japanese patients. Implications: PK parameter estimates of serum IgG were similar between Japanese and non-Japanese patients with PID. The PPK model, updated with Japanese data, was consistent with the previously published PPK model and could accurately predict both individual and population serum IgG concentrationetime profiles following IgPro10 IV infusions every 3 or 4 weeks. EudraCT identifier: 2016-001631-12.

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