Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy

Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy Debora F. Kimberlin, MD,a Stephen Weller, MS,b Richard J. Whitley, MD,a William W. Andrews, PhD, MD,a John C. Hauth, MD,a Fred Lakeman, PhD,a and Gerri Miller, MSb Birmingham, Alabama, and Research Triangle Park, North Carolina 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. STUDY DESIGN: 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 µg/mL vs 0.74 ± 0.6 µg/mL, P < .0001) and at steady state (3.03 ± 1.0 µg/mL vs 0.94 ± 0.7 µg/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 · µg/mL vs 7.71 ± 2.5 h · µg/mL, P < .001) and at steady state (19.65 ± 6.4 h · µg/mL versus 11.0 ± 4.5 h · µg/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. CONCLUSION: 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. (Am J Obstet Gynecol 1998;179:846-51.)

Key words: Acyclovir, genital herpes, herpes simplex virus, pharmacokinetics, pregnancy, valacyclovir

Herpes simplex virus (HSV) infections are among the most frequent of all human viral infections. As many as 3% to 4% of gravid women have a known history of recurrent genital HSV infection.1 The most serious risk posed by genital HSV infection during pregnancy is that of vertical transmission of infection to the fetus or neonate. Intrapartum contact of the fetus with an infected maternal genital tract accounts for approximately 85% of all cases of neonatal herpes. The antepartum management and route of delivery for women with genital herpes infections remain controversial in the United From the Department of Obstetrics and Gynecology, University of Alabama at Birmingham,a and Glaxo-Wellcome, Inc.b Support provided in part by Glaxo Wellcome, Inc. Presented at the Eighteenth Annual Meeting of the Society of Perinatal Obstetricians, Miami, Florida, February 2-7, 1998. Reprint requests: Debora F. Kimberlin, MD, Department of Obstetrics and Gynecology, 618 S 20th St, Old Hillman Building Room 452, Birmingham, AL 35233-7333. Copyright © 1998 by Mosby, Inc. 0002-9378/98 $5.00 + 0 6/6/92965

846

States. To avoid intrapartum HSV exposure and transmission of infection to the neonate, it is recommended that pregnant women with active genital herpes lesions at the time of labor undergo cesarean delivery.2,3 Despite an increasing awareness regarding the epidemiologic characteristics, clinical manifestations, and management of maternal and neonatal herpes, there is still no proven method for prevention of genital HSV shedding at delivery, with subsequent transmission of HSV infection from the mother to the neonate. Acyclovir, a nucleoside analog, is selectively activated in HSV-infected cells and has been proven safe and effective in the treatment of a variety of HSV infections. Daily suppressive acyclovir therapy decreases the frequency of symptomatic genital herpes recurrences in nonpregnant adults.4-8 Data from two prospective trials suggest that acyclovir therapy during late pregnancy decreases the frequency of HSV recurrence at delivery.9,10 The bioavailability of oral acyclovir is only approximately 20%.11 As a result, plasma levels adequate for the

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inhibition of less sensitive herpes viruses have been difficult to achieve. In an effort to achieve higher plasma acyclovir concentrations, prodrugs with minor alterations in the basic structure of acyclovir have been developed. Valacyclovir, the hydrochloride salt of the L-valine ester of acyclovir, is well absorbed from the gastrointestinal tract and rapidly converted to acyclovir by first-pass hydrolysis in the liver. In studies of nonpregnant adults, the bioavailability of acyclovir after the administration of oral valacyclovir is between 3 and 5 times greater than that after the administration of oral acyclovir.12 An added potential benefit of valacyclovir therapy is its once or twice daily dosing; this less frequent dosing may improve compliance. No data are available on valacyclovir therapy during pregnancy. We performed a phase I clinical trial to evaluate the pharmacokinetics and safety of oral valacyclovir suppressive therapy during late gestation in women with recurrent genital HSV infection. Material and methods During the study period, June 1996-August 1997, all women who registered for prenatal care in the Jefferson County Health Departments or University of Alabama at Birmingham Obstetric clinics and had a reported history of recurrent genital HSV infection were found by review of a computerized obstetric database. The study protocol was approved by the Institutional Review Board at the University of Alabama at Birmingham, and informed consent was obtained from all volunteers. Potential study candidates were contacted and referred to our Center for Research in Women’s Health for a screening visit at 34 weeks’ gestation. After they gave informed consent, patients participated in a screening interview and underwent a thorough physical examination. Only women who had both a history of recurrent genital HSV infection antedating pregnancy and documented HSV-2 type-specific serologic antibodies were included. Women who had a history of hepatic disease, renal dysfunction (serum creatinine level >1.5 mg/dL), bone marrow suppression (eg, human immunodeficiency virus seropositivity, malignancy, or immunosuppressive therapy), or known acyclovir intolerance were excluded from the trial. In addition, women whose pregnancies were complicated by multifetal gestation, known fetal anomaly, intrauterine fetal growth restriction, or amniotic fluid volume disturbances (oligohydramnios or polyhydramnios) were also ineligible to participate. Before treatment random assignment, maternal blood samples were obtained to establish the following: HSV (type 1 and 2) serologic status by immunoblot,13 human immunodeficiency virus antibody status, baseline hematologic status (complete blood cell count with differential), hepatic status (aspartate aminotransferase, alanine aminotransferase, and bilirubin), and renal status (serum creatinine, blood urea nitrogen, and urinalysis).

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Ultrasonographic testing was performed to assess fetal anatomy and amniotic fluid volume. Patients who satisfied all study admission criteria were given another appointment to the Center for Research in Women’s Health at 36 weeks’ gestation. Patients were randomly assigned to receive either 500 mg oral valacyclovir twice daily (9 o’clock AM and 9 o’clock PM) or 400 mg oral acyclovir 3 times daily (9 o’clock AM, 3 o’clock PM, and 9 o’clock PM). Patients were seen for weekly study visits from 36 weeks’ gestation until the time of delivery. Ultrasonographic testing was performed for determination of amniotic fluid volume (4-quadrant amniotic fluid index) at each clinic visit. Participants were given diary cards for notation of any adverse medication effects or symptoms of HSV recurrence; these cards were reviewed at each clinic visit. Pharmacokinetic testing was performed at 36 weeks’ gestation for determination of first-dose pharmacokinetics and at 38 weeks’ gestation for determination of steady-state pharmacokinetic parameters. At each of these 2 visits maternal blood samples were obtained immediately before study drug administration and at 0.5, 1, 1.5, 2, 3, 5, 7, and 9 hours after drug administration to determine maternal acyclovir concentrations. Additional maternal blood samples were obtained at the 38-week visit for safety monitoring (complete blood cell count with differential, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, blood urea nitrogen, and urinalysis). At all other weekly study visits blood samples were drawn immediately before and 1 hour after dose administration for pharmacokinetic analysis. When patients were in labor additional maternal blood and urine samples were obtained for safety monitoring (complete blood cell count with differential, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, blood urea nitrogen, and urinalysis). A thorough perineal and sterile speculum examination was performed to assess for clinical evidence of HSV recurrence. Viral specimens were collected from the external genitalia and cervix for HSV culture and detection of HSV deoxyribonucleic acid by polymerase chain reaction. Study medication was continued until delivery. When clinically feasible, simultaneous amniotic fluid and maternal plasma samples were obtained during labor for determination of acyclovir concentrations. Amniotic fluid specimens were obtained by sterile speculum examination with aspiration of pooled fluid from the posterior vaginal fornix. Maternal and umbilical cord blood specimens were collected immediately after delivery for pharmacokinetic analysis. Additional maternal and neonatal blood samples were obtained at 4 and 24 hours after delivery for determination of plasma acyclovir concentrations. At 24 hours after birth, a urine specimen and additional blood samples

848 Kimberlin et al

Fig 1. Mean plasma acyclovir concentrations after initial dose administration (36 weeks’ gestation).

Fig 2. Mean plasma acyclovir concentrations at steady state (38 weeks’ gestation).

(complete blood cell count with differential, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, and blood urea nitrogen) were collected from the neonate for safety assessment, and specimens were obtained from the infant’s conjunctiva, oropharynx, nasopharynx, and rectum for HSV culture and detection of HSV deoxyribonucleic acid by polymerase chain reaction. Patients were asked to bring their infants to the Center for Research in Women’s Health at age 6 months for a follow-up examination. At the 6-month visit, additional infant blood samples were obtained for safety monitoring and a thorough physical examination was performed. To monitor compliance, pills were counted at each weekly study visit and each patient kept a medication log. Results Demographic characteristics. Twenty women were enrolled in the study; 10 were randomly assigned to receive valacyclovir and 10 were randomly assigned to receive acyclovir. Demographic characteristics were similar between the 2 groups, as summarized in Table I.

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Valacyclovir and acyclovir courses ranged between 6 and 40 days (mean 24 days) and between 6 and 37 days (mean 26 days), respectively. Both valacyclovir and acyclovir were generally well tolerated by study participants. There were no serious adverse medication effects detected in either group. Two patients who received acyclovir reported intermittent nausea and headaches; 1 patient who received valacyclovir also reported occasional headaches. These patients’ symptoms were mild and did not interfere with continuation of study medication. Acyclovir and valacyclovir pharmacokinetics. The mean acyclovir concentrations for valacyclovir (n = 10) and acyclovir (n = 10) recipients after administration of the first dose of study drug appear in Fig 1. First-dose pharmacokinetic parameter estimates are summarized in Table II. Steady-state average plasma acyclovir concentrations, obtained at 38 weeks’ gestation, and corresponding pharmacokinetic parameter estimates are shown in Fig 2 and Table III, respectively. Steady-state data were available for 15 patients who had not yet been delivered at 38 weeks’ gestation. The mean peak acyclovir concentrations were significantly higher in valacyclovir recipients than in acyclovir recipients at both sampling intervals. Similarly, the mean values for the daily area under the concentration-time curve, a pharmacokinetic parameter that reflects the daily systemic exposure to a pharmacologic agent, were significantly higher for valacyclovir recipients than for acyclovir recipients. The time to peak concentration and drug elimination half-lives were similar between the 2 groups after the initial dose of study drug and at steady-state testing. Simultaneous amniotic fluid and maternal plasma samples were available for 5 valacyclovir recipients and 4 acyclovir recipients. Acyclovir concentrations (mean ± standard deviation) in amniotic fluid (1.8 ± 2 µg/mL vs 1.3 ± 0.6 µg/mL, P = .67) and maternal plasma (0.92 ± 2 µg/mL vs 0.20 ± 0.3 µg/mL, P = .32) were similar between valacyclovir and acyclovir recipients, respectively. In both patient groups the amniotic fluid acyclovir concentrations were higher than the corresponding maternal plasma acyclovir concentrations. At delivery, maternal and umbilical vein plasma samples were collected. There was a trend toward higher maternal plasma acyclovir concentrations in patients who received valacyclovir than in those who received acyclovir (0.98 ± 1 µg/mL vs 0.15 ± 0.2 µg/mL, P = .08), and umbilical vein plasma acyclovir concentrations were significantly higher in valacyclovir recipients (0.59 ± 0.6 µg/mL vs 0.12 ± 0.10 µg/mL, P = .03). There was no evidence of preferential fetal drug accumulation; umbilical vein plasma acyclovir concentrations were lower than maternal plasma acyclovir concentrations in all mother-infant pairs. The mean ratios between maternal and umbilical vein plasma acyclovir levels were 1.7 and 1.3, respectively, in patients treated with valacyclovir and acyclovir.

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Table I. Demographic characteristics Valacyclovir (n = 10) Age (y)* Race (% black) Parity Multiparous (%) Primiparous (%) Weight (kg)* Height (cm)*

Acyclovir (n = 10)

Table II. Acyclovir first dose (36 weeks) pharmacokinetic parameters Significance

23 ± 4 80

23 ± 4 90

NS NS

100 0 76 ± 23 159 ± 3

80 20 76 ± 20 161 ± 7

NS NS NS

NS, Not significant. *Mean ± SD.

Viral cultures and genital HSV recurrences. No patient had a genital HSV recurrence or asymptomatic HSV shedding (detected by HSV culture or polymerase chain reaction) at delivery. Results of all neonatal cultures and polymerase chain-reaction assays were negative. One patient who received valacyclovir had a symptomatic HSV recurrence before the onset of labor; the patient came to the clinic for evaluation after her lesion had begun to heal. Specimens obtained from the cervix and perineum yielded negative results for HSV culture and polymerase chain reaction. None of the patients who received acyclovir had a symptomatic genital herpes recurrence during the study period, and no woman required cesarean delivery for active genital herpes lesions. Safety assessments. Results of maternal hematologic, renal, and hepatic function tests were normal in all patients at the 34-week screening visit and at 38 weeks’ gestation. One acyclovir recipient had a mildly elevated aspartate amniotransferase activity (127 mg/dL, 3 times normal) at delivery. The specimen was markedly hemolyzed, and this result was not thought to be clinically significant. All other laboratory study results were normal in this patient. At 24 hours after birth, 1 infant whose mother had received valacyclovir had a platelet count of 102,000 cells/mm3, and the specimen was noted to have significant platelet clumping. A platelet count repeated for this infant was normal. At birth, all infants appeared normal and their 5-minute Apgar scores were >8. The hospital course after delivery was uneventful in all the mother-infant pairs. All laboratory study results from the 6-month infant follow-up visits were normal, and no clinical evidence of drug toxicity was observed. Amniotic fluid volumes were monitored weekly during the trial. Mild oligohydramnios (amniotic fluid index 4-5) developed in 2 acyclovir recipients at >41 weeks’ gestation, and these patients subsequently underwent labor induction. Oligohydramnios was considered to be related to advanced gestational age in these 2 patients. A third acyclovir recipient had an amniotic fluid index of 4 at 39 weeks’ gestation. She reported a history of amniotic fluid leakage and underwent an uncomplicated labor in-

Parameter Cmax (µg/mL) Tmax (h) AUC (h · µg/mL) T ⁄ (h) 1

2

Valacyclovir (n = 10)

Acyclovir (n = 10)

Significance

3.1 ± 0.7 1.9 ± 1.8 17.8 ± 3.6 2.0 ± 0.5

0.7 ± 0.6 2.4 ± 1.2 7.7 ± 2.5 2.2 ± 0.5

P < .0001 P = .48 P < .001 P = .47

Cmax, Peak concentration; Tmax, time to peak concentration; AUC, daily area under the concentration-time curve; T ⁄ , elimination half-life. 1

2

Table III. Acyclovir steady-state (38 weeks) pharmacokinetic parameters Parameter

Valacyclovir (n = 7)

Cmax (µg/mL) Tmax (h) AUC (h · µg/mL) T ⁄ (h)

3.0 ± 1.0 1.9 ± 0.9 19.7 ± 6.4 2.6 ± 0.7

1

2

Acyclovir (n = 8)

Significance

0.9 ± 0.7 1.5 ± 0.5 11.0 ± 4.5 3.2 ± 1.0

P < .001 P = .34 P = .009 P = .23

Cmax,, Peak concentration; Tmax,, time to peak concentration; AUC, daily area under the concentration-time curve; T ⁄ , elimination half-life. 1

2

duction. One valacyclovir recipient had decreased amniotic fluid (amniotic fluid index 5.5) between 37 and 38 weeks’ gestation. The study drug was discontinued and the patient was followed up expectantly until 39 weeks’ gestation, when labor was induced. Serial ultrasonography revealed borderline amniotic fluid volumes (amniotic fluid index 6-8) at each visit. All safety screening laboratory values were normal in these 4 mother-infant pairs, and none of the mothers or infants had plasma acyclovir levels significantly higher than those in other acyclovir and valacyclovir recipients. For 3 of the 4 patients a clear obstetric explanation for oligohydramnios was noted; in the fourth case the amniotic fluid index was borderline. Comment In this phase I trial, maternal valacyclovir therapy resulted in higher plasma acyclovir concentrations with significantly greater acyclovir mean plasma concentrations, peak plasma concentrations, and daily area under the concentration-time curve values than seen after acyclovir therapy. Acyclovir was concentrated in the amniotic fluid in valacyclovir and acyclovir recipients; however, there was no evidence of preferential fetal drug accumulation. Both valacyclovir and acyclovir were well tolerated by patients, and no clinical or laboratory evidence of significant drug toxicity was observed. One valacyclovir recipient had a recurrence before delivery; however, none of

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the study participants had either genital HSV recurrence or asymptomatic viral shedding at delivery. The appropriate doses of acyclovir and valacyclovir for use during human pregnancy have not been established. The dose of 400 mg acyclovir 3 times daily was chosen because a previous phase I study on acyclovir use in pregnancy had established a favorable pharmacokinetic profile with this regimen.14 In addition, the largest prospective randomized trial among women with recurrent genital HSV infection found a significant decrease in the frequency of symptomatic HSV recurrence at delivery and in the need for cesarean delivery for HSV with this dose.9 Because no previous data were available for valacyclovir use during pregnancy, we chose to use the manufacturer’s recommended dosage of valacyclovir for treatment of recurrent genital herpes in nonpregnant adults (500 mg twice daily). Despite the extensive maternal physiologic changes that occur during late pregnancy (eg, increased blood volume, renal blood flow, and cardiac output), we found that pharmacokinetic values in these pregnant women were similar to those reported for nonpregnant adults. The pharmacokinetic values that we obtained from patients who received acyclovir were similar to those reported by Frenkel et al14 and Haddad et al15 in previous phase I trials of acyclovir therapy during late pregnancy and to those reported for nonpregnant adults. This is the first clinical trial to evaluate valacyclovir therapy in pregnant women. Among patients who received valacyclovir therapy, the pharmacokinetic values that we obtained were similar to those reported from trials conducted with nonpregnant patients.16 Thus the limited available data suggest that the physiologic changes occurring during late gestation do not significantly alter maternal acyclovir or valacyclovir pharmacokinetics. Of paramount concern is the safety of antiviral therapy for gravid women and their fetuses. In 1984 Glaxo Wellcome, Inc, in collaboration with the Centers for Disease Control, established the Acyclovir in Pregnancy Registry to gather data on prenatal acyclovir exposures. To date, the registry has found neither an increased frequency of congenital anomalies, nor a consistent pattern of the few malformations that have been reported, among >600 fetuses exposed to acyclovir during any trimester of pregnancy.17,18 Furthermore, there are no significant data to indicate that acyclovir is carcinogenic in human beings. No embryotoxic or fetotoxic effects were demonstrated in mouse, rabbit, or rat studies when acyclovir was given in therapeutic doses. 19 Because valacyclovir is rapidly and almost completely converted to acyclovir, safety concerns are similar for the two agents. Acyclovir is excreted by glomerular filtration and tubular secretion,11 and reversible nephrotoxicity may result when either valacyclovir or acyclovir is given in doses significantly higher than those used in this

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trial.20,21 Reported pediatric clinical experience with acyclovir provides indirect evidence of the medication’s safety; the drug is well tolerated by term and preterm infants who receive parenteral therapy.22,23 Furthermore, plasma levels have been reported to be significantly higher among neonates who receive parenteral therapy than among fetuses delivered to women who received oral acyclovir during late pregnancy.14,15 In this phase I trial none of the study participants or their neonates had clinical or laboratory evidence of renal dysfunction or other drug toxicity. These findings are consistent with those reported from other small clinical trials of maternal acyclovir suppressive therapy during late pregnancy.9,10,14,15 Both valacyclovir and acyclovir daily suppressive therapy have been shown to reduce the frequency of genital HSV recurrences in nonpregnant adults.4-8,24 There are limited data on acyclovir therapy in pregnancy, and this is the only trial of valacyclovir suppressive therapy in late gestation to date. Prospective trials by Scott et al9 and Stray-Pedersen10 have suggested that acyclovir therapy during late pregnancy decreases the frequency of genital HSV recurrences at delivery, thereby reducing the frequency of cesarean delivery for HSV. In a decision analysis, Randolph et al25 concluded that oral suppressive acyclovir therapy in late pregnancy was more cost-effective among women with recurrent genital herpes than was the current strategy of cesarean delivery for women who have active herpes lesions during labor. Suppression of genital HSV recurrences with prophylactic antiviral therapy holds promise as an effective interventional strategy for women with a history of recurrent genital herpes. Additional data from large, prospective trials are needed before definitive conclusions can be reached regarding the safety and efficacy of suppressive acyclovir or valacyclovir therapy during late pregnancy.

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