Clinical pharmacokinetics of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine in human immunodeficiency virus-infected patients

The pharmacokinetics and bioavailability of 1-[((S)-2-hydroxy-2-oxo-1,4,2-d ioxaphosphorinan-5-yl)methyl] cytosine (cyclic HPMPC) were examined at four doses in 22 patients with human immunodeficiency virus infection. Two grou ps of sis patients received a single dose of cyclic HPMPC at 1.5 or 3.0 mg/ kg of body weight by each of the oral and intravenous routes in a random or der with a 2-week washout period between administrations, Additional patien ts received single intravenous doses of cyclic HPMPC at 5.0 mg/kg (n = 6) o r 7.5 mg/kg (n = 4). Serial serum and urine samples were collected at inter vals over 24 h after dosing. The concentrations of cyclic HPMPC and cidofov ir in serum and urine samples were determined by validated reverse-phase io n-pairing high-performance liquid chromatography methods with derivatizatio n and fluorescence detection. After intravenous administration of cyclic HP MPC, concentrations of cyclic HPMPC declined in a biexponential manner, wit h a mean +/- standard deviation half-life of 1.09 +/- 0.12 h (n = 22). The pharmacokinetics of cyclic HPMPC were independent of dose over the dose ran ge of 1.5 to 7.5 mg/kg. The total clearance of cyclic HPMPC from serum and the volume of distribution of intravenous cyclic HPMPC were 198 +/- 39.6 ml /h/kg and 338 +/- 65.1 ml/kg, respectively (n = 22). The renal clearance of cyclic HPMPC (132 +/- 27.3 ml/h/kg; 22) exceeded the creatinine clearance (86.2 +/- 16.3 ml/h/kg), indicating active tubular secretion. The cyclic HP MPC excreted in urine in 23 h accounted for 71.3% +/- 16.0% of the administ ered dose. Cidofovir was formed from cyclic HPMPC in vivo with a time to th e maximum concentration in serum of 1.64 +/- 0.23 h (n = 22), Cidofovir lev els declined in an apparent monoexponential manner, with a mean terminal ha lf-life of 3.98 +/- 1.26 h (n = 22), The cidofovir excreted in urine in 23 h accounted for 9.40% +/- 2.33% of the administered cyclic HPMPC dose. Expo sure to cidofovir after intravenous administration of cyclic HPMPC was dose proportional and was 14.9% of that from an equivalent dose of cidofovir. T he present study suggests that intravenous cyclic HPR-IPC also has a lower potential for nephrotoxicity in humans compared to that of intravenous cido fovir, The oral bioavailabilities of cyclic HPMPC were 1.76% +/- 1.38% and 3.10 +/- 1.16% with the administration of doses of 1.5 and 3.0 mg/kg, respe ctively (n = 6 per dose). The maximum concentrations of cyclic HPMPC in ser um were 0.036 +/- 0.021 and 0.082 +/- 0.038 mu g/ml after the oral administ ration of doses of 1.5 and 3.0 mg/kg, respectively. Cidofovir reached quant ifiable levels in the serum of only one patient for each of the 1.5- and 3. 0-mg/kg oral cyclic HPMPC doses.