Lower dose of AZT provides adequate exposure in patients with low body weight
Polly Clayden, HIV i-Base
In Thailand, the standard AZT dose of 300 mg BD has frequently been linked with gastrointestinal intolerance and anaemia. Based on this observation, Thai National Guidelines recommend prescribing AZT at a dose of 200 mg BD in patients less than 60 kg. However, although some studies support AZT administration adjusted for body weight, 200 mg twice daily in patients less than 60 kg has never been formally evaluated.
A poster from Tim Cressey, from the Institut de Recherche pour le Developement, Program for HIV, Chiang Mai, Thailand, reported findings from an intensive PK study of AZT 200mg BD in HIV positive Thai patients initiating a highly active antiretroviral therapy (HAART) regimen.
Antiretroviral naive patients less than 60 kg initiated a regimen of AZT 200 mg lamivudine 150mg, indinavir 600 mg and ritonavir 100 mg BD. At one month from initiation of therapy, blood samples were taken pre-dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 hours after drug intake. Three men and five women were evaluated in this study. Their median age was 38 years (range: 29-41years); weight 54kg (range: 46-59 kg); CD4 count 162 cells/mm3 (range: 88-268 cells/mm3), plasma HIV-1 RNA log10 3.83 copies (range: 2.86-5.59 copies), hemoglobin 12.0 g/dl (10.5-12.3g/dI) and absolute neutrophil 1845 cells/mm3 (1280- 3710 cells/mm3).
At one month, the investigators found the median AZT AUC, Cmax, Tmax and T1/2 were 1.27 mg.h/L (range:1.0-1.88 mg.h/L), 0.56 mg/L (range: 0.34-1.26 mg.h/L), 0.59 hours (range: 0.25-2.1 hours) and 1.11 hours (range: 0.93-3.80 hours), respectively. AZT was undetectable (<25 ng/mL) 8 hours post dose in all patients.
The inter-patient variability (%CV) for AUC, Cmax and Tmax was 21%, 52% and 75%, respectively. There were no differences in AZT PK parameters in blood samples drawn one week later. The investigators found no correlation between weight and PK parameters. Two patients experienced mild anaemia early during the 48 weeks of study follow- up. This resolved without intervention.
AZT 200 mg BD in patients less than 60 kg achieved a plasma exposure only slightly lower than that previously reported for 300 mg BD in non-Asian populations, but a considerable reduction in Cmax was observed. The investigators wrote: This indicates that lower zidovudine dosing can likely provide adequate exposure in patients with low body weight thus possibly reducing the risk of anemia and neutropenia.
It is unclear whether toxicity is related to plasma levels, Cmax or accumulation of intracellular metabolites of AZT.
Cressey T, Leenasirimakul, Jourdain G et al. Intensive pharmacokinetics of zidovudine 200 mg twice daily in HIV-1 infected patients less than 60 kg on highly active antiretroviral therapy. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 24.