Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy.
OBJECTIVE
The objective was to obtain preliminary pharmacokinetic data for acyclovir from gravid women receiving herpes simplex virus suppressive therapy with the acyclovir prodrug valacyclovir.


METHODS
In a prospective, double-blind trial, 20 women with a history of recurrent genital herpes simplex virus infection and positive herpes simplex virus 2 serologic results were randomly assigned at 36 weeks' gestation to receive oral valacyclovir (500 mg twice daily) or acyclovir (400 mg 3 times daily). Acyclovir pharmacokinetic profiles were obtained after the initial dose (36 weeks) and at steady state (38 weeks). Amniotic fluid samples were obtained during labor and simultaneous umbilical cord and maternal plasma samples were collected at delivery. Laboratory studies were performed to screen for laboratory evidence of toxicity in mothers and infants.


RESULTS
Peak acyclovir plasma concentrations (mean +/- standard deviation) were higher in valacyclovir recipients than in acyclovir recipients after the initial dose (3.14 +/- 0.7 microg/mL vs 0.74 +/- 0.6 microg/mL, P < .0001) and at steady state (3.03 +/- 1.0 microg/mL vs 0.94 +/- 0.7 microg/mL, P < .001). The daily area under the curve values were higher in valacyclovir recipients than acyclovir recipients after the initial dose (17.8 +/- 3.6 h x microg/mL vs 7.71 +/- 2.5 h x microg/mL, P < .001) and at steady state (19.65 +/- 6.4 h x microg/mL versus 11.0 +/- 4.5 h x microg/mL, P = .009). There was no significant difference in drug elimination half-life or in time to peak concentration between valacyclovir and acyclovir recipients at either sampling interval. Acyclovir was concentrated in the amniotic fluid; however, there was no evidence of preferential fetal drug accumulation (mean maternal/umbilical vein plasma ratios at delivery were 1.7 for valacyclovir and 1.3 for acyclovir). Valacyclovir was well tolerated, and no significant laboratory or clinical evidence of toxicity was detected.


CONCLUSIONS
In this phase I trial maternal valacyclovir therapy resulted in higher plasma acyclovir levels, with significantly higher peak concentrations and daily area under the curve values, than did acyclovir therapy. Additional trials are needed to further evaluate the safety and efficacy of suppressive valacyclovir therapy during late pregnancy.
Kimberlin
D F
DF
Department of Obstetrics and Gynecology, University of Alabama at Birmingham, USA.
Weller
S
S
Whitley
R J
RJ
Andrews
W W
WW
Hauth
J C
JC
Lakeman
F
F
Miller
G
G
D000212:Acyclovir / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents; D004311:Double-Blind Method; D005260:Female; D005865:Gestational Age; D006558:Herpes Genitalis / Q000188:drug therapy*; D018258:Herpesvirus 2, Human; D006801:Humans; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy / Q000821:virology*; D011446:Prospective Studies; D012008:Recurrence; D000077483:Valacyclovir; D014633:Valine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000998:Antiviral Agents; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir