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Population pharmacokinetics and pharmacodynamics of zidovudine, didanosine and nevirapine in children and adolescents with advanced HIV disease

Author

Yong Ho Kim, University of the Pacific

Date of Award

2000

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Paul Williams

First Committee Member

Patrick Catania

Second Committee Member

Donald Floriddia

Third Committee Member

Arthur Harralson

Fourth Committee Member

Coburn Ward

Abstract

The population pharmacokinetics and pharmacodynamics (PK/PD) of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in 432 pediatric patients with HIV, randomized to receive either a double-therapy of ZDV + ddI or NVP + ddI; or triple-therapy of NVP + ZDV + ddI as a substudy of the AIDS Clinical Trials Group Protocol 245 in 2 phases. In phase 1, nonlinear mixed-effect modeling (NONMEM) analysis was employed for population pharmacokinetics (PPK) study for ZDV, ddI and NVP. One-compartment model with first-order input and first-order elimination was fitted to the NVP, ZDV and ddI data. Final PPK models were as follows: ZDV; CL (1/hr, without nevirapine coadministration) = 52.4 × BSA, CL (1/hr, with nevirapine coadministration) = 65.0 × BSA, Vd/F(1) = 116 × BSA, ddI; CL (1/hr) = 73.4 × BSA + 69.9, Vd/F(1) = 132, and NVP; CL (1/hr) = 2.30 × BSA, Vd/F(1) = 120. In phase 2, the relationship between the predicted serum concentrations of ZDV, ddI, and NVP and pharmacodynamic responses were evaluated via S-Plus ® exploratory data analysis. No apparent relationship between average steady-state serum concentrations and pharmacodynamic variables, such as HIV-1 RNA(RNA) levels, CD4 + count was found. However, the responses of RNA level and CD4 + count to the double therapy (ddI/NVP) versus triple therapy (ddI/NVP/ZDV) were significantly different after 4 weeks of therapy ( P = 0.0014 for RNA level at week 4, P = 0.0454 for CD4 + count at week 12). No significantly different responses were found in weight changes ( P > 0.25 at all weeks). Also, the maximum drop of RNA level throughout the treatment period had a strong relationship to the decline slope of RNA at week 4 as follows: Maximum drop of RNA = 3.1139 × RNA decline slope at week 4 - 0.411. Nevirapine dosing regimens were compared using simulation via Trial Simulator™. Both ACTG regimen (body surface area based) and manufacture's regimen (age and weight based) produced similar concentrations at lower end concentration but manufacture's regimen produce higher concentration at upper end with 1000 simulated patients (ACTG regimen; 2150, 3827, and 4992 ng/ml, manufacturer's regimen; 2066, 4130, and 6568 ng/ml, for 10 th , 50 th , and 96 th percentile, respectively). It is suggested to use body surface area based dosing regimen for NVP.

Pages

191

ISBN

9780599940161 , 0599940166

Recommended Citation

Kim, Yong Ho. (2000). Population pharmacokinetics and pharmacodynamics of zidovudine, didanosine and nevirapine in children and adolescents with advanced HIV disease. University of the Pacific, Dissertation - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/2722