PHARMACOKINETICS OF ORAL VALACYCLOVIR AND ACYCLOVIR IN LATE PREGNANCY

OBJECTIVE: The objective was to obtain preliminary pharmacokinetic dat a for acyclovir from gravid women receiving herpes simplex virus suppr essive therapy with the acyclovir prodrug valacyclovir. STUDY DESIGN: In a prospective, double-blind trial, 20 women with a history of recur rent genital herpes simplex virus infection and positive herpes simple x virus 2 serologic results were randomly assigned at 36 weeks' gestat ion to receive oral valacyclovir (500 mg twice daily) or acyclovir (40 0 mg 3 times daily). Acyclovir pharmacokinetic profiles were obtained after the initial dose (36 weeks) and at steady state (38 weeks). Amni otic fluid samples were obtained during labor and simultaneous umbilic al cord and maternal plasma samples were collected at delivery. Labora tory studies were performed to screen for laboratory evidence of toxic ity in mothers and infants. RESULTS: Peak acyclovir plasma concentrati ons (mean +/- standard deviation) were higher in valacyclovir recipien ts than in acyclovir recipients after the initial dose (3.14 +/- 0.7 m u g/mL vs 0.74 +/- 0.6 mu g/mL, P < .0001) and at steady state (3.03 /- 10 mu g/mL vs 0.94 +/- 0.7 mu g/mL, P < .001). The daily area under the curve values were higher in valacyclovir recipients than acyclovi r recipients after the initial dose (17.8 +/- 3.6 h.mu g/mL vs 7.71 +/ - 2.5 h.mu g/mL, P < .001) and at steady state (19.65 +/- 6.4 h.mu g/m L versus 11.0 +/- 4.5 h.mu g/mL, P = .009). There was no significant d ifference in drug elimination half-lib or in time to peak concentratio n between valacyclovir and acyclovir recipients at either sampling int erval. Acyclovir was concentrated in the amniotic fluid; however, ther e was no evidence of preferential fetal drug accumulation (mean matern al/umbilical vein plasma ratios at delivery were 1.7 for valacyclovir and 1.3 for acyclovir). Valacyclovir was well tolerated, and no signif icant laboratory or clinical evidence of toxicity was detected. CONCLU SION: In this phase I trial maternal valacyclovir therapy resulted in higher plasma acyclovir levels. with significantly higher peak concent rations and daily area under the curve values, than did acyclovir ther apy. Additional trials are needed to further evaluate the safety and e fficacy of suppressive valacyclovir therapy during late pregnancy.