Lowering zidovudine (AZT) dosing to 200mg twice daily could reduce toxicity and remain effective for HIV-positive individuals who weigh less than 60kg, according to the results of a small pharmacokinetic study from Thailand, published as a letter in the July issue of the Journal of AIDS. The study authors argue that fixed-dose combination tablets with reduced zidovudine dosages should be made available for resource-limited settings.
International guidelines for antiretroviral treatment in resource-limited settings currently recommend a zidovudine dose of 600mg daily. However, due to the observation that many patients in Thailand have experienced gastrointestinal intolerance and anaemia at this dose, the Thai National Guidelines recommend dosing zidovudine at 200mg twice daily in individuals who weigh less than 60kg.
A previous single-dose pharmacokinetic study of zidovudine at 300 mg twice daily in 20 Thai patients weighing a median of 53 kg reported zidovudine exposure that was approximately 5-fold of that observed in heavier, Caucasian patients. However, since this dose has not been formally studied for tolerability and efficacy, investigators from Harvard University and Chiang Mai, Thailand conducted an intensive pharmacokinetic study of zidovudine in three men and five women, with a median age of 38, weighing a median of 54 kg.
All eight individuals were treatment-naive and starting a first-line potent antiretroviral therapy regimen that consisted of zidovudine 200mg, lamivudine (3TC) 150mg, and ritonavir-boosted indinavir (Crixivan) 600mg/100mg, all twice daily. Baseline CD4 count was 162 cells/mm3 and median viral load was 3.83 log10 copies/ml.
After one month of treatment, where adherence was found to be greater than 95% for all patients (assessed by exact pill count), blood samples were taken pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours after taking the drugs with food. Sampling was done in exactly the same way a week later.
Although there was some interpatient variability for zidovudine levels at both visits, drug levels were not significantly different for each patient at either visit. The investigators observed no significant linear relationship between weight and zidovudine area under the curve (AUC), maximum observed concentration (Cmax), and oral clearance (CL/F). Zidovudine levels were undetectable after eight hours.
When they compared zidovudine exposure with published data in heavier patients (mean weight 74 kg) who had taken Trizivir (300mg zidovudine/150mg lamivudine/300mg abacavir) twice daily, the investigators observed similar drug levels, with the exception of an approximately 2-fold reduction in the Thai patients' Cmax and a lower CL/F. "Assuming that the remaining zidovudine levels eight hours postdose have little effect on the Cmax," the investigators write, "the lower Cmax observed is consistent with 200mg zidovudine dosed three times daily."
After one month of zidovudine the investigators noted a median decrease in median haemoglobin level of 2.1 g/dl from a baseline of 12.0g/dl. In addition, two of the patients experienced mild anaemia, but this resolved without intervention. The investigators note that zidovudine exposure levels in these two patients were not significantly higher than that of the other patients.
Seven of the eight patients remained on this combination for 48 weeks (one patient switched due to indinavir toxicity). After 48 weeks of follow-up all seven achieved and maintained a viral load below 400 copies/mL.
The investigators write that they recognise the limitations of measuring zidovudine plasma concentrations since, "they poorly reflect the 'active' intracellular zidovudine triphosphate levels", but say that a more complex assay "was not feasible". They note, however, "it is likely that minimal zidovudine plasma concentrations are required to achieve minimal intracellular concentrations; therefore, the measurements of zidovudine plasma concentrations are informative."
They conclude by asserting that "zidovudine 200mg twice daily in Thai patients less than 60kg achieved plasma exposure similar to 300mg twice daily in heavier patients and was well tolerated in the long term, and there was no evidence to suggest a decreased efficacy."
They suggest that reducing the zidovudine dose to 200mg twice daily in patients with low weight may be a "reasonable strategy....especially in settings with limited alternative nucleoside analogues", and argue that their "data advocate for considering fixed-dose combination tablets with reduced zidovudine dosages."
Cressey TR et al. Intensive pharmacokinetics of zidovudine 200 mg twice daily in HIV-1 infected patients weighing less than 60kg on highly active antiretroviral therapy. JAIDS 42 (3), 387-388, 2006.