HTB

TDM for individualising dosing – practicality and efficacy for PIs and RTIs

Simon Collins, HIV i-Base

Courtney Fletcher, from the University of Minnesota, is one of the key pharmacologists in the US who currently prioritises this area of research. Dr Fletcher provided up-dated data from one of several of his studies presented at the last ICAAC.

The primary aim of this randomised open label study was to evaluate the safety and feasibility of individually adjusted concentration controlled (CC) regimens, compared to standard dosing (STD). All patients received AZT/3TC/indinavir. Intensive PK studies were performed at weeks 2, 28, and 56 if eligible, and steady-state target concentrations were 0.19mg/l for AZT, 0.44mg/l for 3TC and a Cmin of 0.15 mg/l for indinavir. Dose adjustments included TID dosing for AZT and 3TC and occasionally QID dosing for indinavir. In addition to a statistically significant improvement in obtaining optimum dosing concentrations shown below the median time taken to reach undetectable HIV RNA (<50 copies) was 110 days in the CC arm compared to 176 days in the STD dosed arm.

Table 1

Drug % Patients achieving target dose
Standard dosing Concentration controlled dosing
AZT 8/13 (62%) 11/11 (100%) *
3TC 10/13 (77%) 11/11 (100%)
DV 3/13 (23%) I 9/11 (82%) *

Table 2

Time to BLQ (<50) BLQ at wk 24
Standard dosing 176 days 9/13 (75%)
Concentration controlled dosing 110 days * 10/11 (91%)

* p = 0.056 (Mantel-Cox)

Adherence was monitored by count of returned pills (patients were provided with medication for several additional days with each monthly supply), and was found to be equal in both arms, despite more complicated regimens in the CC arm.

Secondary aims of this study involved quantitating intracellular AZT- and 3TC- triphosphate, which are more critical to nucleoside activity, and the relationship to antiretroviral response. Results from 8 subjects (with a total of 69 paired plasma and PBMC samples) found no relationship between plasma clearance of AZT and 3TC but a significant correlation between PBMC concentrations of the triphosphate levels of each drug (r=0.7, p<0.001). Lower CD4 baseline was also found to lead to higher triphosphate levels and the rate of HIV RNA decline correlated with higher levels of TP in each drug. [1]

Reference:

  1. Fletcher C et al. Concentration Controlled Antiretroviral Therapy. Abstract 6.2. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.

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