AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 9, NUMBER 4 July 1992
ZIDOVUDINE PHARMACOKINETICS DURING PREGNANCY Rhoda S. Sperling, M.D., John Roboz, Ph.D., Renata Dische, M.D., Ph.D., Demetra Silides, M.S., Ian Holzman, M.D., and Edward Jew, M.D.
ABSTRACT
Zidovudine (ZDV, 3'-Azido-2',3'-dideoxythymidine, AZT) is a potent inhibitor of viral reverse transcriptase. In vitro studies have shown that it has substantial activity against the human immunodeficiency virus (HIV).1 The use of ZDV in pregnancy, either for the treatment of maternal symptomatic HIV disease23 or for the possible prevention of perinatal HIV transmission,4-6 raises questions about effective drug dosing in pregnancy. To date, only limited ZDV pharmacokinetic data in pregnancy have been reported.78 We report results of pharmacokinetic studies from an HIV-1 infected pregnant woman receiving ZDV therapy.
Downloaded by: University of British Columbia. Copyrighted material.
As the indications for zidovudine (ZDV) treatment in human immunodeficiency virus-infected individuals expand, we anticipate an increased use of this drug during pregnancy. We report pharmacokinetics data from a patient studied both in the third trimester and intrapartum. ZDV peak-plasma levels and serum half-lives were comparable to nonpregnant adults. High concentrations of ZDV and its glucuronide metabolite were found in umbilical cord blood and in amniotic fluid.
duced. The induction was uncomplicated and she delivered a morphologically normal female infant: weight, 2550 gm; height, 47 cm; head circumference, 33 cm; and Apgar scores, 9 and 9 at 1 and 5 minutes, respectively. There was no newborn anemia: cord blood hematocrit, 64%; newborn (day 1) hemoglobin, 15.0 gm/dl and hematocrit, 44.7%. Examination of the placenta revealed a 410 gm term placenta with focal subchorionitis and chorioamnionitis. Focal calcifications were present. No other abnormalities were noted.
PHARMACOKINETICS STUDIES CASE REPORT
A 3 2-year-old para 0010 was diagnosed as HIV-1 seropositive 1 year prior to her pregnancy. She was a heterosexual contact of an at-risk male. Her past medical history was unremarkable. Prior to this pregnancy, she began treatment with ZDV, 900 mg/day (500 mg/m2/day), because of a depressed CD4+ (T-helper) cell count that was less than 200 cells/mm3. In addition, she was placed on daily trimethoprim (160 mg)/sulfamethoxazole (800 mg) as prophylaxis for Pneumocystis carinii pneumonia. The patient elected to continue both therapies throughout gestation. There was no maternal hematologic toxicity observed during pregnancy. Persistent macrocytic indices, consistent with ZDV therapy, were noted on all maternal blood counts. The pregnancy was uncomplicated. Serial sonography performed every 4 weeks demonstrated good fetal growth with adequate amniotic fluid. At 38 weeks, after spontaneous rupture of membranes, labor was in-
Methods
Concentrations of ZDV and its glucuronide metabolite (GZDV) were determined in serum from both maternal and cord blood, amniotic fluid, and breast milk by a modified version of a published high-performance liquid chromatographic technique.9 The modification consisted of replacing the resin extraction stage by ultrafiltration through a microconcentrator with 30 kd cutoff (Centricon-30, Amicon Co., Danvers, MA) followed by the direct injection of aliquots. The 3'-(3-azido stereoisomer of ZDV was used as internal standard at a concentration of 1500 ng/ml. Calibration curves were obtained using fluids from normal subjects after supplementing with increasing quantities of ZDV and GZDV. Homogenates of placental tissue were analyzed for the presence of ZDV and GZDV These were prepared by homogenizing, in a glass-to-glass homogenizer placed into an ice bath, tissue samples of 40 to 170 mg size to which an
Departments of Obstetrics, Gynecology and Reproductive Science, Neoplastic Diseases, Pathology, and Pediatrics, The Mount Sinai School of Medicine, New York, New York Reprint requests: Dr. Sperling, Box 1173, Mount Sinai Medical Center, 1 Gustave Levy Place, New York, NY 10029 Copyright © 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
247
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 9, NUMBER 4 July 1992 Table 1. Zidovudine (ZDV) and Its Glucuronide Metabotite (GZDU) Concentration in Various Maternal Fluids and Tissues
ZDV GZDV (ng/ml)* (ng/ml)
Source RESULTS
The first pharmacokinetic study was made at 32 weeks' gestation. Figure 1 shows the elimination of ZDV and GZDV after a 200 mg oral dose of ZDV. The GZDV concentration at zero time was 590 ng/ml because the patient was already on a steady-state oral regimen. The residual concentration of GZDV at 4 hours was 110 ng/ml (not well seen in the figure). Figure 2 shows elimination curves intrapartum after a 140 mg intravenous dose of ZDV. The residual concentration of GZDV at 10.2 hours was 100 ng/ml. Table 1 summarizes additional samples tested from the mother. ZDV and GZDV elimination curves for the newborn are shown in Figure 3. In Figure 3, the broken line indicates that extrapolation to zero concentration of GZDV would be at approximately 14 hours. Neither ZDV nor GZDV were detected when the last sample was obtained at 25 hours.
Maternal serum (at delivery) Umbilical vein Umbilical artery Amniotic fluid before ZDV infusion Amniotic fluid 2 hours after ZDV infusion Breast milk 14 hours after ZDV infusion Placenta
210 200 280 480 820
1120 1270 1330 8230 5040
ND+
ND
70
110
*To convert from ng/ml to |xmol/liter multiply by 0.0037 for ZDV and 0.0021 for GZDV. +ND: not detected.
7500 T
Figure 1. Maternal serum elimination curves for zidovudine (ZDV, •) and its glucuronide metabolite (GZDV, A) after a 200 mg oral dose of ZDV given at 32 weeks (mother of steady state of oral dose regimen). Residual GZDV at 4 hours was 110 ng/ml (not clearly shown in the figure).
2500 n
248
Figure 2. Maternal serum elimination curves for zidovudine (ZDV, •) and its glucuronide metabolite (GZDV, A) after a 140 mg intravenous dose of ZDV given 2 hours before delivery. Residual GZDV at 10.2 hours was 100 ng/ml (not clearly shown in the figure.) The arrows show concentrations of ZDV and GZDV at the time of del ivery (see also Table 1).
Downloaded by: University of British Columbia. Copyrighted material.
appropriate quantity of phosphate buffered saline (pH 7.2) was added to achieve a final tissue concentration of approximately 5%. Placental tissue from normal deliveries were used as controls.
ZIDOVUDINE DURING PREGNANCY/Sperling, et al. 1200 n
en c
DISCUSSION ZDV pharmacokinetic studies in nonpregnant adults have demonstrated peak plasma levels of 810 to 1080 ng/ml (3 to 4 ^M) 30 to 90 minutes after a single 200 mg oral dose1011 with a serum half-life of approximately 1.1 hours.1112 After maternal oral and intravenous doses, the ZDV elimination curves were comparable to nonpregnant adults.10-12 Both ZDV and its inactive metabolite, GZDV, were rapidly cleared from the maternal circulation. In contrast, the elimination of ZDV and GZDV was markedly reduced in the newborn (Fig. 3) compared with the mother. Table 1 summarizes the ZDV and GZDV concentrations found in other tissues and fluids. Despite ZDV therapy throughout gestation and intrapartum, ZDV was not concentrated in placental tissue. Also, ZDV was not found in breast milk. Transplacental passage of ZDV has already been reported by others.7-8 In agreement with these reports, both ZDV and GZDV were found in high concentrations in cord blood and in amnioticfluid.7-8The concentration of ZDV in the umbilical artery and vein were nearly identical to maternal concentration. In the amniotic fluid, even higher concentrations of ZDV and GZDV were found. Thus, significant fetal exposure will occur when maternal therapy is given. In the fetus there is concern about teratogenic effects, hematologic toxicity, and longterm developmental effects. In both pediatric and adult treatment trials, ZDV has resulted in myelosuppression;13-14 whether myelosuppression can occur in the developing fetus after transplacental passage of ZDV is a potential risk. A system of ongoing case surveillance is needed to identify any ZDV-associated fetal toxicities that may result from maternal therapy.
REFERENCES Burroughs-Wellcome. Retrovir (zidovudine) product monograph. Research Triangle Park. The Wellcome Foundation, May 1988 Fischl MA, Richman DD, Griero MH, et al: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex; a double-blind, placebocontrolled trial. N Engl J Med 317:192-197, 1987
3. Volberbing PA, Lagakos SW, Koch MA, et al: Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4 positive cells per cubic millimeter. N Engl J Med 322:941-949, 1990 4. Ruprecht RM, O'Brien LG, Rossoni LD, Lehrman SN: Suppression of mouse viraemia and retroviral disease by 3'-azido-3'-deoxythymidine. Nature 323:467-467, 1986 5. Tavares L, Roneker C, Johnston K, Lehrman SN, deNoronha, F: 3'-Azido-3'-deoxythymidine in feline leukemia virus infected cats: A model for therapy and prophylaxis of AIDS. Cancer Res 47:3190-3194, 1987 6. McClure HM, Anderson DC, Fulz P, Ansar A, Brodie A, Lehrman S: Prophylactic effects of AZT following exposure of macaques to an acutely lethal variant of SIV. V International Conference on AlDS, Montreal, Canada, 1989 7. Chauanet P, Diquet B, Waldner A, et al: Perinatal pharmacokinetics of zidovudine. (Letter.) N Engl J Med 321:14581549,1989 8. Gillet JY, Garraffo R, Abrar D, et al: Fetoplacental passage of zidovudine. (Letter.) Lancet 2:269-270, 1989 9. Good S, Reynolds P, DeMiranda P: Simultaneous quantification of zidovudine and its glucuronide in serum by highperformance liquid chromatography. J Chromatogr 431: 123-133,1989 10. Yarchoan R, Klecker RW, Weinhold KJ, et al: Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLVIII/LAV replication to patients with AIDS or AIDSrelated complex. Lancet 1:575-580, 1986 11. Klecker RW, Collins JM, Yarchoan RC, et al: Plasma and cerebrospinal fluid pharmacokinetics of 3'-deoxythymidine: A novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther 41:407-412, 1987 12. Blum MR, Liao SH, Good SS, deMiranda P: Pharmacokinetics and bioavailability of zidovudine in humans. Am J Med 85(Suppl 2A): 189-194, 1988 13. Richman DD, Fischl MA, Grieco MH, et al: The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex; a double-blind, placebocontrolled trial. N Engl J Med 317:185-189, 1987 14. Pizzo PA, Eddy J, Falloon J, et al: Effects of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 319: 889-896, 1988 Funded in part by National Institutes of Health 1U01Al-27554-02 and by The T.J. Martell Foundation for Cancer, Leukemia, and AIDS Research. 249
Downloaded by: University of British Columbia. Copyrighted material.
Figure 3. Newborn serum elimination curves for zidovudine (ZDV, •) and its glucuronide metabolite (GZDV, A), beginning 30 minute after birth. The broken line indicates that extrapolation to zero concentration, for GZDV, would probably be at 14 hours. Note that both ZDV and GZDV were determined as nondetectable at 25 hours.
ZIDOVUDINE PHARMACOKINETICS DURING PREGNANCY Rhoda S. Sperling, M.D., John Roboz, Ph.D., Renata Dische, M.D., Ph.D., Demetra Silides, M.S., Ian Holzman, M.D., and Edward Jew, M.D.
ABSTRACT
Zidovudine (ZDV, 3'-Azido-2',3'-dideoxythymidine, AZT) is a potent inhibitor of viral reverse transcriptase. In vitro studies have shown that it has substantial activity against the human immunodeficiency virus (HIV).1 The use of ZDV in pregnancy, either for the treatment of maternal symptomatic HIV disease23 or for the possible prevention of perinatal HIV transmission,4-6 raises questions about effective drug dosing in pregnancy. To date, only limited ZDV pharmacokinetic data in pregnancy have been reported.78 We report results of pharmacokinetic studies from an HIV-1 infected pregnant woman receiving ZDV therapy.
Downloaded by: University of British Columbia. Copyrighted material.
As the indications for zidovudine (ZDV) treatment in human immunodeficiency virus-infected individuals expand, we anticipate an increased use of this drug during pregnancy. We report pharmacokinetics data from a patient studied both in the third trimester and intrapartum. ZDV peak-plasma levels and serum half-lives were comparable to nonpregnant adults. High concentrations of ZDV and its glucuronide metabolite were found in umbilical cord blood and in amniotic fluid.
duced. The induction was uncomplicated and she delivered a morphologically normal female infant: weight, 2550 gm; height, 47 cm; head circumference, 33 cm; and Apgar scores, 9 and 9 at 1 and 5 minutes, respectively. There was no newborn anemia: cord blood hematocrit, 64%; newborn (day 1) hemoglobin, 15.0 gm/dl and hematocrit, 44.7%. Examination of the placenta revealed a 410 gm term placenta with focal subchorionitis and chorioamnionitis. Focal calcifications were present. No other abnormalities were noted.
PHARMACOKINETICS STUDIES CASE REPORT
A 3 2-year-old para 0010 was diagnosed as HIV-1 seropositive 1 year prior to her pregnancy. She was a heterosexual contact of an at-risk male. Her past medical history was unremarkable. Prior to this pregnancy, she began treatment with ZDV, 900 mg/day (500 mg/m2/day), because of a depressed CD4+ (T-helper) cell count that was less than 200 cells/mm3. In addition, she was placed on daily trimethoprim (160 mg)/sulfamethoxazole (800 mg) as prophylaxis for Pneumocystis carinii pneumonia. The patient elected to continue both therapies throughout gestation. There was no maternal hematologic toxicity observed during pregnancy. Persistent macrocytic indices, consistent with ZDV therapy, were noted on all maternal blood counts. The pregnancy was uncomplicated. Serial sonography performed every 4 weeks demonstrated good fetal growth with adequate amniotic fluid. At 38 weeks, after spontaneous rupture of membranes, labor was in-
Methods
Concentrations of ZDV and its glucuronide metabolite (GZDV) were determined in serum from both maternal and cord blood, amniotic fluid, and breast milk by a modified version of a published high-performance liquid chromatographic technique.9 The modification consisted of replacing the resin extraction stage by ultrafiltration through a microconcentrator with 30 kd cutoff (Centricon-30, Amicon Co., Danvers, MA) followed by the direct injection of aliquots. The 3'-(3-azido stereoisomer of ZDV was used as internal standard at a concentration of 1500 ng/ml. Calibration curves were obtained using fluids from normal subjects after supplementing with increasing quantities of ZDV and GZDV. Homogenates of placental tissue were analyzed for the presence of ZDV and GZDV These were prepared by homogenizing, in a glass-to-glass homogenizer placed into an ice bath, tissue samples of 40 to 170 mg size to which an
Departments of Obstetrics, Gynecology and Reproductive Science, Neoplastic Diseases, Pathology, and Pediatrics, The Mount Sinai School of Medicine, New York, New York Reprint requests: Dr. Sperling, Box 1173, Mount Sinai Medical Center, 1 Gustave Levy Place, New York, NY 10029 Copyright © 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
247
AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 9, NUMBER 4 July 1992 Table 1. Zidovudine (ZDV) and Its Glucuronide Metabotite (GZDU) Concentration in Various Maternal Fluids and Tissues
ZDV GZDV (ng/ml)* (ng/ml)
Source RESULTS
The first pharmacokinetic study was made at 32 weeks' gestation. Figure 1 shows the elimination of ZDV and GZDV after a 200 mg oral dose of ZDV. The GZDV concentration at zero time was 590 ng/ml because the patient was already on a steady-state oral regimen. The residual concentration of GZDV at 4 hours was 110 ng/ml (not well seen in the figure). Figure 2 shows elimination curves intrapartum after a 140 mg intravenous dose of ZDV. The residual concentration of GZDV at 10.2 hours was 100 ng/ml. Table 1 summarizes additional samples tested from the mother. ZDV and GZDV elimination curves for the newborn are shown in Figure 3. In Figure 3, the broken line indicates that extrapolation to zero concentration of GZDV would be at approximately 14 hours. Neither ZDV nor GZDV were detected when the last sample was obtained at 25 hours.
Maternal serum (at delivery) Umbilical vein Umbilical artery Amniotic fluid before ZDV infusion Amniotic fluid 2 hours after ZDV infusion Breast milk 14 hours after ZDV infusion Placenta
210 200 280 480 820
1120 1270 1330 8230 5040
ND+
ND
70
110
*To convert from ng/ml to |xmol/liter multiply by 0.0037 for ZDV and 0.0021 for GZDV. +ND: not detected.
7500 T
Figure 1. Maternal serum elimination curves for zidovudine (ZDV, •) and its glucuronide metabolite (GZDV, A) after a 200 mg oral dose of ZDV given at 32 weeks (mother of steady state of oral dose regimen). Residual GZDV at 4 hours was 110 ng/ml (not clearly shown in the figure).
2500 n
248
Figure 2. Maternal serum elimination curves for zidovudine (ZDV, •) and its glucuronide metabolite (GZDV, A) after a 140 mg intravenous dose of ZDV given 2 hours before delivery. Residual GZDV at 10.2 hours was 100 ng/ml (not clearly shown in the figure.) The arrows show concentrations of ZDV and GZDV at the time of del ivery (see also Table 1).
Downloaded by: University of British Columbia. Copyrighted material.
appropriate quantity of phosphate buffered saline (pH 7.2) was added to achieve a final tissue concentration of approximately 5%. Placental tissue from normal deliveries were used as controls.
ZIDOVUDINE DURING PREGNANCY/Sperling, et al. 1200 n
en c
DISCUSSION ZDV pharmacokinetic studies in nonpregnant adults have demonstrated peak plasma levels of 810 to 1080 ng/ml (3 to 4 ^M) 30 to 90 minutes after a single 200 mg oral dose1011 with a serum half-life of approximately 1.1 hours.1112 After maternal oral and intravenous doses, the ZDV elimination curves were comparable to nonpregnant adults.10-12 Both ZDV and its inactive metabolite, GZDV, were rapidly cleared from the maternal circulation. In contrast, the elimination of ZDV and GZDV was markedly reduced in the newborn (Fig. 3) compared with the mother. Table 1 summarizes the ZDV and GZDV concentrations found in other tissues and fluids. Despite ZDV therapy throughout gestation and intrapartum, ZDV was not concentrated in placental tissue. Also, ZDV was not found in breast milk. Transplacental passage of ZDV has already been reported by others.7-8 In agreement with these reports, both ZDV and GZDV were found in high concentrations in cord blood and in amnioticfluid.7-8The concentration of ZDV in the umbilical artery and vein were nearly identical to maternal concentration. In the amniotic fluid, even higher concentrations of ZDV and GZDV were found. Thus, significant fetal exposure will occur when maternal therapy is given. In the fetus there is concern about teratogenic effects, hematologic toxicity, and longterm developmental effects. In both pediatric and adult treatment trials, ZDV has resulted in myelosuppression;13-14 whether myelosuppression can occur in the developing fetus after transplacental passage of ZDV is a potential risk. A system of ongoing case surveillance is needed to identify any ZDV-associated fetal toxicities that may result from maternal therapy.
REFERENCES Burroughs-Wellcome. Retrovir (zidovudine) product monograph. Research Triangle Park. The Wellcome Foundation, May 1988 Fischl MA, Richman DD, Griero MH, et al: The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex; a double-blind, placebocontrolled trial. N Engl J Med 317:192-197, 1987
3. Volberbing PA, Lagakos SW, Koch MA, et al: Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4 positive cells per cubic millimeter. N Engl J Med 322:941-949, 1990 4. Ruprecht RM, O'Brien LG, Rossoni LD, Lehrman SN: Suppression of mouse viraemia and retroviral disease by 3'-azido-3'-deoxythymidine. Nature 323:467-467, 1986 5. Tavares L, Roneker C, Johnston K, Lehrman SN, deNoronha, F: 3'-Azido-3'-deoxythymidine in feline leukemia virus infected cats: A model for therapy and prophylaxis of AIDS. Cancer Res 47:3190-3194, 1987 6. McClure HM, Anderson DC, Fulz P, Ansar A, Brodie A, Lehrman S: Prophylactic effects of AZT following exposure of macaques to an acutely lethal variant of SIV. V International Conference on AlDS, Montreal, Canada, 1989 7. Chauanet P, Diquet B, Waldner A, et al: Perinatal pharmacokinetics of zidovudine. (Letter.) N Engl J Med 321:14581549,1989 8. Gillet JY, Garraffo R, Abrar D, et al: Fetoplacental passage of zidovudine. (Letter.) Lancet 2:269-270, 1989 9. Good S, Reynolds P, DeMiranda P: Simultaneous quantification of zidovudine and its glucuronide in serum by highperformance liquid chromatography. J Chromatogr 431: 123-133,1989 10. Yarchoan R, Klecker RW, Weinhold KJ, et al: Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLVIII/LAV replication to patients with AIDS or AIDSrelated complex. Lancet 1:575-580, 1986 11. Klecker RW, Collins JM, Yarchoan RC, et al: Plasma and cerebrospinal fluid pharmacokinetics of 3'-deoxythymidine: A novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin Pharmacol Ther 41:407-412, 1987 12. Blum MR, Liao SH, Good SS, deMiranda P: Pharmacokinetics and bioavailability of zidovudine in humans. Am J Med 85(Suppl 2A): 189-194, 1988 13. Richman DD, Fischl MA, Grieco MH, et al: The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex; a double-blind, placebocontrolled trial. N Engl J Med 317:185-189, 1987 14. Pizzo PA, Eddy J, Falloon J, et al: Effects of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med 319: 889-896, 1988 Funded in part by National Institutes of Health 1U01Al-27554-02 and by The T.J. Martell Foundation for Cancer, Leukemia, and AIDS Research. 249
Downloaded by: University of British Columbia. Copyrighted material.
Figure 3. Newborn serum elimination curves for zidovudine (ZDV, •) and its glucuronide metabolite (GZDV, A), beginning 30 minute after birth. The broken line indicates that extrapolation to zero concentration, for GZDV, would probably be at 14 hours. Note that both ZDV and GZDV were determined as nondetectable at 25 hours.
