Intensive Pharmacokinetics of Zidovudine 200 mg Twice Daily in HIV-1-Infected Patients Weighing Less Than 60 kg on Highly Active Antiretroviral Therapy

To the Editor: Despite its widespread use and published guidelines, the optimal dose for zidovudine is unknown. Since its introduction, zidovudine dosing has rapidly evolved. Initial clinical trials administered zidovudine 1500 mg/d (250 mg, every 4 hours), but significant hematological toxicity was observed.1,2 Reduced daily doses of zidovudine were then tested,3,4 and currently, in international guidelines, the recommended zidovudine dose is 600 mg/d in 2 or 3 divided doses.5 However, in Thailand, zidovudine 300 mg twice daily has been frequently associated with gastrointestinal intolerance and anemia; and based on their experience, Thai experts recommend in the National Guidelines zidovudine 200 mg twice daily in patients less than 60 kg.6 Excessive zidovudine drug exposure may explain the poor tolerability of the dose of 300 mg twice daily, especially in patients with low body weights. Indeed, a single-dose pharmacokinetic study of zidovudine (300 mg) in 20 Thai patients (median weight, 53 kg) reported zidovudine exposure approximately 5-fold that observed in white patients.7 Furthermore, zidovudine oral clearance has been reported to be significantly lower in patients with lower body weight,8 although other data have reported no linear relationship.9 In population analyses, body weight has also been shown to be an important covariate in estimation of zidovudine clearance.10 Thus, studies support zidovudine administration adjusted for body weight, but 200 mg twice daily in patients less than 60 kg has not been formally studied. We conducted an intensive pharmacokinetics study of zidovudine in 8 HIV-infected Thai patients (3 men and 5 women) initiating a highly active antiretroviral therapy regimen that included zidovudine 200 mg twice daily. The samples analyzed in this study were collected to compare the pharmacokinetic parameters of zidovudine, lamivudine, and 2 reduced doses of indinavir boosted with ritonavir; the results of the pharmacokinetic analysis for reduced dose of indinavir boosted with ritonavir have been published.11 HIV-infected, treatment-naive adults at Nakornping Hospital, Chiang Mai, were proposed to undergo baseline evaluations after providing written informed consent. Patients less than 60 kg initiated zidovudine 200 mg, lamivudine 150 mg, indinavir 600 mg, and ritonavir 100 mg twice daily. After 1 month, blood samples were taken at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 hours after drug intake. To allow for the comparison of 2 indinavir doses, pharmacokinetic assessment was repeated 1 week later following the same blood draw schedule. All drugs were taken with food at the pharmacokinetic sampling visits. Adherence was assessed by exact pill count and was greater than 95% for all patients. This study was approved by the Ethics Committee at the Faculty of Associated Medical Sciences, Chiang Mai University. Zidovudine plasma drug concentrations were measured by high-performance liquid chromatography (T. King, L.R. Bushman, C.V. Fletcher; Assay method for the simultaneous determination of 3TC, DDI, D4T, ZDV, and ABC in human plasma by reversed-phase UV HPLC; personal communication; University of Colorado Health Sciences Center; 2003.) at the Faculty of Associated Medical Sciences, which participates in the Pharmacology Quality Control program of the AIDS Clinical Trial Group, USA. Data were analyzed with WinNonLin (Pharsight) using noncompartment methods: the parameters calculated were maximum observed concentration (Cmax), observed time to maximum concentration (Tmax), minimum observed concentration, elimination rate constant, apparent oral clearance (CL/F), and apparent volume of distribution. Area under the concentration time cure (AUC) was calculated using the trapezoidal rule. A Wilcoxon signed rank test was used to compare the pharmacokinetic parameters calculated between blood sampling visits. The relationship between body weight, the independent variable, and zidovudine pharmacokinetic parameters, the dependant variables, was analyzed by simple linear least-squares regression. A P value < 0.05 was considered significant. At baseline, median (range) age was 38 years (29-41), weight 54 kg (46-59), CD4 count 162 cells/mm3 (88-268), plasma HIV-1 RNA log10 3.83 copies/mL (2.86-5.59), hemoglobin 12.0 g/dL (10.5-12.3), absolute neutrophil count 1845 cells/mm3 (1280-3710), creatinine 0.8 mg/dL (0.7-1.1), and alanine aminotransferase 38 U/L (26-69). Table 1 shows the pharmacokinetic values and interpatient variability for zidovudine at both intensive pharmacokinetic sampling visits. Zidovudine pharmacokinetic parameters were not significantly different between the sampling visits. Zidovudine plasma levels were not detectable (above 25 ng/mL) 8 hours postdose. No significant linear relationship between weight and zidovudine pharmacokinetic parameters (AUC, Cmax, and CL/F) was observed.TABLE 1: Steady-State Pharmacokinetic Parameters of Zidovudine 200 mg Twice Daily as Part of Highly Active Antiretroviral Therapy in HIV-Infected Thai Patients Less Than 60 kgAfter 1 month of zidovudine 200 mg twice daily treatment, a median decrease in hemoglobin level of 2.1 g/dL (-0.8 to -3.3) was observed. Two patients experienced mild anemia early during the 48 weeks of study follow-up, which resolved without intervention. Zidovudine exposures in these 2 patients were not significantly higher than those in the other patients. Although the efficacy of the zidovudine 200 mg twice daily could not be directly assessed, 7 of 8 patients remained on the same highly active antiretroviral therapy regimen through 48 weeks of follow-up, one patient switched because of indinavir toxicity, and all maintained their viral load <400 copies/mL.11 Comparing the zidovudine exposure with published data in patients (mean weight 74 kg) on Trizivir (300 mg zidovudine/150 mg lamivudine/300 mg abacavir b.i.d.)12 (Table 1), similar levels were achieved, although coadministration of abacavir and zidovudine can slightly reduce zidovudine Cmax (20%) and delay Tmax (0.5 hours).13 An approximate 2-fold reduction in the Thai patient's Cmax was observed along with a lower CL/F. Assuming that the remaining zidovudine levels 8 hours postdose have little effect on the Cmax, the lower Cmax observed is consistent with 200 mg zidovudine dosing 3 times daily (Table 1).14 We recognize that zidovudine plasma concentrations poorly reflect the "active" intracellular zidovudine triphosphate levels, but because of the complexity of the assay and the need for large blood volumes, assessment was not feasible. 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. In summary, zidovudine 200 mg twice daily in Thai patients less than 60 kg achieved plasma exposure similar to 300 mg twice daily in heavier patients and was well tolerated in the long term, and there was no evidence to suggest a decreased efficacy. To help reduce zidovudine-associated toxicities, the option of a zidovudine dose reduction, especially in settings with limited alternative nucleoside analogues, may be a reasonable strategy in patients with low body weight. Furthermore, this data advocate for considering fixed-dose combination tablets with reduced zidovudine dosages. ACKNOWLEDGMENT This work was supported by the Institut de Recherche pour le Développement (IRD), URI 174. Zidovudine for the antiretroviral drug assay was obtained through the NIH AIDS Research and Reference Program, Division of AIDS, NIAID, NIH. Tim R. Cressey, PhD*† Prattana Leenasirimakul, MD‡ Gonzague Jourdain, MD, PhD*† Yardpiroon Tawon, BSc† Pra-ornsuda Sukrakanchana, RN† Marc Lallemant, MD*† *Harvard School of Public Health Harvard University, Boston, MA †Institut de Recherche pour le Développement (IRD), Program for HIV Prevention and Treatment, UR 174 and ‡Nakornping Provincial Hospital Chiang Mai, Thailand [email protected]