HAAS DW, WELLER S, JOHNSON B, NICOTERA J, LUTHER JM, BROUMAND V, GOOD K, STEIN DS; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. A-1796.

Vanderbilt Univ., Nashville, TN.

BACKGROUND: Reversible neurological adverse events (CNS AEs) are rarely associated with ACV or its prodrug VACV, most often in patients with severe renal impairment. ACV is eliminated mostly unchanged by renal excretion, along with the metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-9-[(2-hydroxyethoxy)methyl]guanine (8OH-ACV). It has been hypothesized that selective CNS accumulation of CMMG is responsible for CNS AEs, although there are no published data on its pharmacokinetic (PK) profiles in serum or CSF. METHODS: Oral VACV 2000mg q6h was administered to 6 subjects with normal renal function (NRF group; CLcr > 75 mL/min) and VACV 1500mg q12h was given to 3 subjects with renal impairment (RI group; CLcr 15-30 mL/min). After the 5th dose, serial samples of blood and CSF (via intrathecal catheter) were obtained over an entire dosing interval t (= 6 or 12 h) in each subject. Validated assays measured ACV by RIA and metabolites by mass spectrometry. PK analysis was performed by non-compartmental methods. RESULTS: Mean (SD) steady-state PK parameter estimates: [table: see text]. For the NRF group, CSF penetration [mean (SD) of CSF/serum AUCt ratios] was 0.27 (0.05) for ACV, 0.025 (0.011) for CMMG, and 0.25 (0.05) for 8OH-ACV. Values for the RI subjects were similar at 0.28 (0.03) for ACV, 0.025 (0.003) for CMMG and 0.19 (0.02) for 8OH-ACV. There were no serious or drug related AEs. CONCLUSIONS: CSF penetration ratios of ACV (~28%), CMMG (~2.5%) and 8OH-ACV (~23%) appear independent of renal function. Total ACV metabolites were 2.0% of ACV exposure in CSF for NRF subjects and 4.3% for RI subjects, and are unlikely to result in CNS AEs.

Publication Types:

• Meeting Abstracts

Keywords:

• 9-carboxymethoxymethylguanine
• Acyclovir
• Guanine
• Humans
• Kidney Diseases
• Pharmaceutical Preparations
• Prodrugs
• Radioimmunoassay
• Valine
• administration & dosage
• organization & administration
• pharmacokinetics
• valacyclovir

Other ID:

• GWAIDS0024966

UI: 102264590

From Meeting Abstracts