Oseltamivir for the Treatment of H1N1 Influenza During Pregnancy RH Beigi1,2, VC Pillai3, R Venkataramanan2,3,4 and SN Caritis1,2 Pregnancy heightens the risk of adverse outcomes from influenza infections. This is true for both seasonal epidemics as well as occasional pandemics. Seasonal influenza vaccines are the focus of disease prevention and are recommended for all pregnant women in any trimester of pregnancy and postpartum. Oseltamivir (Tamiflu) is currently the recommended and most commonly used pharmaceutical agent for influenza prophylaxis and treatment. Oseltamivir has been demonstrated to prevent disease after exposure, treat infected individuals, as well as lessen the likelihood of complications. The physiologic adaptations of pregnancy alter the pharmacokinetics of this important drug. Evidence of these alterations, knowledge gaps, and future investigative directions to fill these knowledge gaps are highlighted. Pregnant women have increased susceptibilities to severe infection and worse clinical outcomes from influenza. These heightened risks are noted both during seasonal epidemics as well as the occasional pandemic, including the recent 2009 H1N1 experience.1 Appropriately, much attention is focused on use of the inactivated vaccine for primary prevention of influenza in pregnancy. However, the modest efficacy and marginal uptake of influenza vaccine in pregnancy continue to highlight the importance of optimizing the use of antiviral medications such as oseltamivir (Tamiflu) against influenza exposure and disease given its demonstrated efficacy.1 BASIC INDICATIONS AND PHARMACOLOGY OF OSELTAMIVIR
Neuraminidase inhibitor drugs (oseltamivir, zanamivir, peramivir, etc.) are competitive inhibitors of the neuraminidase (NA) enzyme on the influenza virus, acting on sialic acid residues. Blocking this surface receptor enzyme prevents the release of infectious virus from host cells, limiting the propagation of infection. Currently, both oseltamivir and zanamivir are recommended for the prevention and treatment of influenza among exposed and/or infected individuals, respectively. The current recommended doses of oseltamivir and zanamivir are 75 mg as an oral capsule and 10 mg as a dry powder inhaler, respectively, taken daily for 7–10 days after exposure (prevention dose), and 75 mg tablet and 10 mg powder inhaler twice daily, respectively, for 5 days (treatment dose).1 Due to the fact that pregnant
women are almost completely excluded from participation in clinical trials of new therapeutic agents, no pharmacologic data have been generated in this population during the drug development or advanced clinical trial phase investigations of oseltamivir (or zanamivir). Thus, at the outset of the recent 2009 H1N1 influenza pandemic scant data were available to inform optimal use of these critically important antiviral agents in this vulnerable patient population. Even less data existed for zanamivir in pregnancy and clinical use of zanamivir was less often chosen, thus the focus was on oseltamivir. Oseltamivir phosphate (OP) is an orally administered prodrug that is well absorbed. It then undergoes significant conversion by hepatic carboxylesterases (carboxylesterase-1) to the single active metabolite oseltamivir carboxylate (OC) (Figure 1).2 Only 5% of OP is excreted unchanged in the urine. Earlier pharmacokinetic (PK) studies in healthy subjects following oral administration of oseltamivir phosphate and intravenous administration of OC suggest that 80% of orally administered oseltamivir reaches systemic circulation as active metabolite.3 Peak plasma concentrations of OC are achieved in 2–4 hours and the PK of OC appears to be linear across a large dose range. OC is exclusively eliminated by renal excretion, with an elimination half-life in the range of 6–10 hours, and there are minimal known drug–drug interactions. Given the known marked effects of pregnancy on the functions of the gastrointestinal, hepatic, and renal systems, biologic plausibility exists for altered PK of oseltamivir with subsequent implications for dosing recommendations.4 Moreover,
1
Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; 2Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 3Department of Pharmaceutical Sciences, School of Pharmacy, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 4Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Correspondence: RH Beigi ([email protected]) Received 18 May 2015; accepted 19 June 2015; advance online publication 25 June 2015. doi:10.1002/cpt.179 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 98 NUMBER 4 | OCTOBER 2015
403
Figure 1 Structure of oseltamivir parent drug (OP) and active metabolite (OC).
given the noted increased likelihood of untoward outcomes from influenza in pregnancy, precise data regarding PK (and ideally pharmacodynamics (PD)) are warranted and of significant importance in this population. AVAILABLE INVESTIGATIONS
To fill this large data gap, investigations were undertaken by the National Institutes of Health’s (NIH) Obstetric-Fetal Pharmacologic Research Unit (OPRU) Network, as well as others.5–7 In addition to the potential impact on efficacy due to PK alterations, antimicrobial agents also have the additional consideration of the potential for drug resistance from subtherapeutic levels, further emphasizing the importance of investigations to determine optimal dosing. Both investigations used an "opportunistic" study design, enrolling pregnant women already on treatment courses of oseltamivir for influenza. This study design does pose some challenges because of the inability to alter the dosing schedule; however, it is an effective way of obtaining modest amounts of data in pregnancy, given that women are already receiving drug. Such an approach can also minimize some of the logistical barriers to performing research on therapeutics in pregnancy. The OPRU network study enrolled 29 pregnant women receiving oseltamivir treatment and across all gestational ages along with 35 nonpregnant contemporaneous controls (who ingested oseltamivir solely for study purposes).5,6 This design offered the advantage of having a comparator population of nonpregnant women providing data within the same investigation, thus undergoing the same statistical and methodological approach. Eighty-nine percent of the pregnant women were on oseltamivir for treatment of influenza or influenza-like illness (mostly on standard twice daily doses) and the remaining 11% were on the 75 mg once-daily prophylactic dose. Despite these differences in dosing within the pregnant cohort, all women in both cohorts underwent intensive PK sampling after being on oseltamivir therapy for at least 48 hours. Dose-adjusted PK data were used in this investigation to control for these noted differences in schedule. It was found that the physiologic changes of pregnancy produced an 30% lower exposure (2,786 6 879 ng/ ml*hr vs. 3,840 6 1,117 ng/ml*hr, P 5 0.0001) to the active metabolite OC when compared to nonpregnant women. These pharmacologic changes correlated with the increased apparent oral drug clearance, presumably from the enhanced renal elimination in pregnancy. Importantly, in these investigations the renal excretion of oseltamivir exceeded the glomerular filtration rate (GFR), suggesting 404
that tubular secretion via an organic anion transporter (OAT) is likely a contributing factor.8 Although there are no direct data on the impact of pregnancy and specific gestational age on human OAT activity in the kidney, the increase in activity can be indirectly inferred from a previously reported PK study of amoxicillin in pregnant women.9 The renal clearance of amoxicillin is significantly reduced by probenecid, suggesting that amoxicillin is a substrate of OATs. Both renal clearance and renal secretion of amoxicillin is increased by more than 50% during the second and third trimester of pregnancy. Additionally, the renal secretion was reported to account for more than 50% of the renal clearance of amoxicillin. This observation suggests that OAT activity is increased during pregnancy. Therefore, it is assumed that the renal secretion of OC (also a substrate of OAT) is increased along with increased GFR during pregnancy, leading to decreased systemic exposure of OC in pregnant women. These findings suggest that altered dosing schedules among pregnant women may be required to better approximate the drug exposure among nonpregnant subjects, although the exact clinical impact of such an approach remains poorly understood. Definitive recommendations regarding pregnancy-specific dosing await further investigation, given the modest sample size. An additional benefit provided by these data are the ability to now perform various pharmacologic modeling investigations that aim to better define the precise pharmacology of this important antiviral drug. Such investigations combined with ongoing and future clinical investigations will likely enable more robust evidence-based recommendations for oseltamivir dosing schedules in pregnancy. A related yet distinct opportunistic investigation was carried out by Greer et al.7 and published contemporaneously with the previous investigation. These researchers looked at the PK of oseltamivir in pregnancy with the primary aim of defining and comparing potential trimester-specific differences in drug metabolism. Thirty women (10 per trimester) were enrolled and all were taking either the usual adult recommended treatment dose of 75 mg twice daily or the prophylactic dose of 75 mg once daily. Unlike the OPRU study, blood sampling occurred before and after the first dose of drug. This group did not find significant differences in the usual PK parameters (Cmax, Tmax, AUC0–12) for the parent prodrug when comparing different gestational ages. Similarly, when they looked at the active metabolite OC they noted similar PK by trimester, with the only finding of Cmax being statistically higher in the third trimester. Moreover, it was suggested that despite these small fluctuations, values were well within the available pharmacologic range for clinical efficacy against circulating strains of influenza, and thus the findings were mostly of academic importance. The final conclusion reached by these investigators is that the PK of oseltamivir (and its active metabolite OC) does not differ significantly by trimester.7 However, it should be noted that this study was not performed at steady state. Given the combination of noted findings in both available studies it appears that formal recommendations addressing potential dosing alterations await clinical data informing the impact of the noted PK-based alterations. VOLUME 98 NUMBER 4 | OCTOBER 2015 | www.wileyonlinelibrary/cpt
An additional important consideration for oseltamivir in pregnancy (as well as any pharmacologic agent used in pregnant women) is safety of the drug and its potential to cross the placenta. The available safety data in animals suggest that use of oseltamivir at clinically recommended dosages is unlikely to pose any adverse effects on fetal growth and development.10 Additionally, more recently available observational studies also fail to suggest that clinical use in pregnancy is of any real concern.11–14 The most important message is that given the known increased risk to pregnant women and their fetuses/newborns from influenza infection (and the absence of data suggesting deleterious effects) treatment with oseltamivir should be prioritized in this patient population. A recent case report addressed the issue of placental perfusion and suggested that OC will traverse the placenta and be detected in the fetal compartment, although at substantially lower levels than in the maternal circulation.15 More specifically, a separate investigation using a dual placental perfusion study reveals that fetal to maternal concentration ratio of oseltamivir carboxylate is 0.35 6 0.075.16 Although it appears that a fraction of the drug may in fact get to the fetus, the full implications of these findings remain to be fully evaluated and are unlikely to be detrimental in any clinically relevant fashion. It should also be emphasized that currently the relationship between the previously noted PK findings of oseltamivir (in both the general and pregnant populations) and their direct PD implications are not fully understood. Because of the potential severity of influenza in varied populations (including pregnant women), the potential for antiviral resistance, and the need to optimize antiviral treatment, this indeed is an obviously important endpoint to delineate. Investigators have suggested a theoretical model that might approximate the relationship using an in vitro surrogate system.17 It has been proposed that the variable AUC24:IC50 might be a useful surrogate endpoint permitting improved PD approximations with correlations to PK. While intriguing, the overall value of this proposal remains to be better delineated.
CONFLICT OF INTEREST The authors declared no conflict of interest.
C 2015 American Society for Clinical Pharmacology and Therapeutics V
1. 2. 3.
4.
5.
6.
7. 8.
9.
10.
11.
12.
13.
14.
CONCLUSION
Oseltamivir is a critically important pharmacologic agent for use in pregnant women due to the heightened risks of influenza in pregnancy. The pharmacology of this important drug in pregnancy is beginning to be fully understood and these findings suggesting a lower overall exposure during pregnancy can be used to shape future investigations aimed at delineating optimal use. Such future investigations should provide for more evidence-based care of this important and uniquely susceptible patient population.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 98 NUMBER 4 | OCTOBER 2015
15.
16.
17.
Beigi, R.H. Prevention and management of influenza in pregnancy. Obstet. Gynecol. Clin. North Am. 41, 535–546 (2014). Dutkowski, R. et al. Safety and pharmacology of oseltamivir in clinical use. Drug Saf. 26, 787–801 (2003). He, G., Massarella, J. & Ward, P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64–0802. Clin. Pharmacokinet. 37, 471–484 (1999). Anderson, G.D. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin. Pharmacokinet. 44, 989–1008 (2005). Beigi, R.H. et al. Pharmacokinetics of oseltamivir among pregnant and nonpregnant women. Am. J. Obstet. Gynecol. 204, S84–88 (2011). Pillai, V.C. et al. Population pharmacokinetics of oseltamivir in nonpregnant and pregnant women. Br. J. Clin. Pharmacol. (2015); e-pub ahead of print. doi: 10.1111/bcp.12691. Greer, L.G. et al. Pharmacokinetics of oseltamivir according to trimester of pregnancy. Am. J. Obstet. Gynecol. 204, S89–S93 (2011). Hill, G. et al. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretioncorrelation of in vivo and in vitro studies. Drug Metab. Dispos. 30, 13–19 (2002). Andrew, M.A. et al. Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies. Clin. Pharmacol. Ther. 81, 547–556 (2007). Donner, B., Niranjan, V. & Hoffmann, G. Safety of oseltamivir in pregnancy: a review of preclinical and clinical data. Drug Saf. 33, 631–642 (2010). Tanaka, T., Nakajima, K., Murashima, A., Garcia-Bournissen, F. & Koren, G. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breasfeeding women. CMAJ 181, 55–58 (2009). Greer, L.G. et al. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet. Gynecol. 115, 711–716 (2010). Xie, H.Y. et al. Infant outcomes among pregnant women who used oseltamivir for treatment of influenza during the H1N1 epidemic. Am. J. Obstet. Gynecol. 208, 293.e1–7 (2013). Saito, S. et al. Outcomes of infants exposed to oseltamivir or zanamivir in utero during pandemic (H1N1) 2009. Am. J. Obstet. Gynecol. 209, 130.e1–9 (2013). Meijer, W.J. et al. Oseltamivir and its active metabolite cross the placenta at significant levels. Clin. Infect. Dis. 54, 1676–1677 (2012). Nanovskaya, T.N., Patrikeeva, S., Zhan, Y., Hankins, G.D. & Ahmed, M.S. Transplacental transfer of oseltamivir carboxylate. J. Matern. Fetal Neonatal. Med. 25, 2312–2315 (2012). McSharry, J.J., Weng, Q., Brown, A., Kulaway, R. & Drusano, G.L. Prediction of the pharmacodynamically linked variable of oseltamivir carboxylate for influenza A virus using an in vitro hollow-fiber infection model system. Antimicrob. Agents Chemother. 53, 2375–2381 (2009).
405
Neuraminidase inhibitor drugs (oseltamivir, zanamivir, peramivir, etc.) are competitive inhibitors of the neuraminidase (NA) enzyme on the influenza virus, acting on sialic acid residues. Blocking this surface receptor enzyme prevents the release of infectious virus from host cells, limiting the propagation of infection. Currently, both oseltamivir and zanamivir are recommended for the prevention and treatment of influenza among exposed and/or infected individuals, respectively. The current recommended doses of oseltamivir and zanamivir are 75 mg as an oral capsule and 10 mg as a dry powder inhaler, respectively, taken daily for 7–10 days after exposure (prevention dose), and 75 mg tablet and 10 mg powder inhaler twice daily, respectively, for 5 days (treatment dose).1 Due to the fact that pregnant
women are almost completely excluded from participation in clinical trials of new therapeutic agents, no pharmacologic data have been generated in this population during the drug development or advanced clinical trial phase investigations of oseltamivir (or zanamivir). Thus, at the outset of the recent 2009 H1N1 influenza pandemic scant data were available to inform optimal use of these critically important antiviral agents in this vulnerable patient population. Even less data existed for zanamivir in pregnancy and clinical use of zanamivir was less often chosen, thus the focus was on oseltamivir. Oseltamivir phosphate (OP) is an orally administered prodrug that is well absorbed. It then undergoes significant conversion by hepatic carboxylesterases (carboxylesterase-1) to the single active metabolite oseltamivir carboxylate (OC) (Figure 1).2 Only 5% of OP is excreted unchanged in the urine. Earlier pharmacokinetic (PK) studies in healthy subjects following oral administration of oseltamivir phosphate and intravenous administration of OC suggest that 80% of orally administered oseltamivir reaches systemic circulation as active metabolite.3 Peak plasma concentrations of OC are achieved in 2–4 hours and the PK of OC appears to be linear across a large dose range. OC is exclusively eliminated by renal excretion, with an elimination half-life in the range of 6–10 hours, and there are minimal known drug–drug interactions. Given the known marked effects of pregnancy on the functions of the gastrointestinal, hepatic, and renal systems, biologic plausibility exists for altered PK of oseltamivir with subsequent implications for dosing recommendations.4 Moreover,
1
Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; 2Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 3Department of Pharmaceutical Sciences, School of Pharmacy, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 4Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Correspondence: RH Beigi ([email protected]) Received 18 May 2015; accepted 19 June 2015; advance online publication 25 June 2015. doi:10.1002/cpt.179 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 98 NUMBER 4 | OCTOBER 2015
403
Figure 1 Structure of oseltamivir parent drug (OP) and active metabolite (OC).
given the noted increased likelihood of untoward outcomes from influenza in pregnancy, precise data regarding PK (and ideally pharmacodynamics (PD)) are warranted and of significant importance in this population. AVAILABLE INVESTIGATIONS
To fill this large data gap, investigations were undertaken by the National Institutes of Health’s (NIH) Obstetric-Fetal Pharmacologic Research Unit (OPRU) Network, as well as others.5–7 In addition to the potential impact on efficacy due to PK alterations, antimicrobial agents also have the additional consideration of the potential for drug resistance from subtherapeutic levels, further emphasizing the importance of investigations to determine optimal dosing. Both investigations used an "opportunistic" study design, enrolling pregnant women already on treatment courses of oseltamivir for influenza. This study design does pose some challenges because of the inability to alter the dosing schedule; however, it is an effective way of obtaining modest amounts of data in pregnancy, given that women are already receiving drug. Such an approach can also minimize some of the logistical barriers to performing research on therapeutics in pregnancy. The OPRU network study enrolled 29 pregnant women receiving oseltamivir treatment and across all gestational ages along with 35 nonpregnant contemporaneous controls (who ingested oseltamivir solely for study purposes).5,6 This design offered the advantage of having a comparator population of nonpregnant women providing data within the same investigation, thus undergoing the same statistical and methodological approach. Eighty-nine percent of the pregnant women were on oseltamivir for treatment of influenza or influenza-like illness (mostly on standard twice daily doses) and the remaining 11% were on the 75 mg once-daily prophylactic dose. Despite these differences in dosing within the pregnant cohort, all women in both cohorts underwent intensive PK sampling after being on oseltamivir therapy for at least 48 hours. Dose-adjusted PK data were used in this investigation to control for these noted differences in schedule. It was found that the physiologic changes of pregnancy produced an 30% lower exposure (2,786 6 879 ng/ ml*hr vs. 3,840 6 1,117 ng/ml*hr, P 5 0.0001) to the active metabolite OC when compared to nonpregnant women. These pharmacologic changes correlated with the increased apparent oral drug clearance, presumably from the enhanced renal elimination in pregnancy. Importantly, in these investigations the renal excretion of oseltamivir exceeded the glomerular filtration rate (GFR), suggesting 404
that tubular secretion via an organic anion transporter (OAT) is likely a contributing factor.8 Although there are no direct data on the impact of pregnancy and specific gestational age on human OAT activity in the kidney, the increase in activity can be indirectly inferred from a previously reported PK study of amoxicillin in pregnant women.9 The renal clearance of amoxicillin is significantly reduced by probenecid, suggesting that amoxicillin is a substrate of OATs. Both renal clearance and renal secretion of amoxicillin is increased by more than 50% during the second and third trimester of pregnancy. Additionally, the renal secretion was reported to account for more than 50% of the renal clearance of amoxicillin. This observation suggests that OAT activity is increased during pregnancy. Therefore, it is assumed that the renal secretion of OC (also a substrate of OAT) is increased along with increased GFR during pregnancy, leading to decreased systemic exposure of OC in pregnant women. These findings suggest that altered dosing schedules among pregnant women may be required to better approximate the drug exposure among nonpregnant subjects, although the exact clinical impact of such an approach remains poorly understood. Definitive recommendations regarding pregnancy-specific dosing await further investigation, given the modest sample size. An additional benefit provided by these data are the ability to now perform various pharmacologic modeling investigations that aim to better define the precise pharmacology of this important antiviral drug. Such investigations combined with ongoing and future clinical investigations will likely enable more robust evidence-based recommendations for oseltamivir dosing schedules in pregnancy. A related yet distinct opportunistic investigation was carried out by Greer et al.7 and published contemporaneously with the previous investigation. These researchers looked at the PK of oseltamivir in pregnancy with the primary aim of defining and comparing potential trimester-specific differences in drug metabolism. Thirty women (10 per trimester) were enrolled and all were taking either the usual adult recommended treatment dose of 75 mg twice daily or the prophylactic dose of 75 mg once daily. Unlike the OPRU study, blood sampling occurred before and after the first dose of drug. This group did not find significant differences in the usual PK parameters (Cmax, Tmax, AUC0–12) for the parent prodrug when comparing different gestational ages. Similarly, when they looked at the active metabolite OC they noted similar PK by trimester, with the only finding of Cmax being statistically higher in the third trimester. Moreover, it was suggested that despite these small fluctuations, values were well within the available pharmacologic range for clinical efficacy against circulating strains of influenza, and thus the findings were mostly of academic importance. The final conclusion reached by these investigators is that the PK of oseltamivir (and its active metabolite OC) does not differ significantly by trimester.7 However, it should be noted that this study was not performed at steady state. Given the combination of noted findings in both available studies it appears that formal recommendations addressing potential dosing alterations await clinical data informing the impact of the noted PK-based alterations. VOLUME 98 NUMBER 4 | OCTOBER 2015 | www.wileyonlinelibrary/cpt
An additional important consideration for oseltamivir in pregnancy (as well as any pharmacologic agent used in pregnant women) is safety of the drug and its potential to cross the placenta. The available safety data in animals suggest that use of oseltamivir at clinically recommended dosages is unlikely to pose any adverse effects on fetal growth and development.10 Additionally, more recently available observational studies also fail to suggest that clinical use in pregnancy is of any real concern.11–14 The most important message is that given the known increased risk to pregnant women and their fetuses/newborns from influenza infection (and the absence of data suggesting deleterious effects) treatment with oseltamivir should be prioritized in this patient population. A recent case report addressed the issue of placental perfusion and suggested that OC will traverse the placenta and be detected in the fetal compartment, although at substantially lower levels than in the maternal circulation.15 More specifically, a separate investigation using a dual placental perfusion study reveals that fetal to maternal concentration ratio of oseltamivir carboxylate is 0.35 6 0.075.16 Although it appears that a fraction of the drug may in fact get to the fetus, the full implications of these findings remain to be fully evaluated and are unlikely to be detrimental in any clinically relevant fashion. It should also be emphasized that currently the relationship between the previously noted PK findings of oseltamivir (in both the general and pregnant populations) and their direct PD implications are not fully understood. Because of the potential severity of influenza in varied populations (including pregnant women), the potential for antiviral resistance, and the need to optimize antiviral treatment, this indeed is an obviously important endpoint to delineate. Investigators have suggested a theoretical model that might approximate the relationship using an in vitro surrogate system.17 It has been proposed that the variable AUC24:IC50 might be a useful surrogate endpoint permitting improved PD approximations with correlations to PK. While intriguing, the overall value of this proposal remains to be better delineated.
CONFLICT OF INTEREST The authors declared no conflict of interest.
C 2015 American Society for Clinical Pharmacology and Therapeutics V
1. 2. 3.
4.
5.
6.
7. 8.
9.
10.
11.
12.
13.
14.
CONCLUSION
Oseltamivir is a critically important pharmacologic agent for use in pregnant women due to the heightened risks of influenza in pregnancy. The pharmacology of this important drug in pregnancy is beginning to be fully understood and these findings suggesting a lower overall exposure during pregnancy can be used to shape future investigations aimed at delineating optimal use. Such future investigations should provide for more evidence-based care of this important and uniquely susceptible patient population.
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 98 NUMBER 4 | OCTOBER 2015
15.
16.
17.
Beigi, R.H. Prevention and management of influenza in pregnancy. Obstet. Gynecol. Clin. North Am. 41, 535–546 (2014). Dutkowski, R. et al. Safety and pharmacology of oseltamivir in clinical use. Drug Saf. 26, 787–801 (2003). He, G., Massarella, J. & Ward, P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64–0802. Clin. Pharmacokinet. 37, 471–484 (1999). Anderson, G.D. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin. Pharmacokinet. 44, 989–1008 (2005). Beigi, R.H. et al. Pharmacokinetics of oseltamivir among pregnant and nonpregnant women. Am. J. Obstet. Gynecol. 204, S84–88 (2011). Pillai, V.C. et al. Population pharmacokinetics of oseltamivir in nonpregnant and pregnant women. Br. J. Clin. Pharmacol. (2015); e-pub ahead of print. doi: 10.1111/bcp.12691. Greer, L.G. et al. Pharmacokinetics of oseltamivir according to trimester of pregnancy. Am. J. Obstet. Gynecol. 204, S89–S93 (2011). Hill, G. et al. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretioncorrelation of in vivo and in vitro studies. Drug Metab. Dispos. 30, 13–19 (2002). Andrew, M.A. et al. Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies. Clin. Pharmacol. Ther. 81, 547–556 (2007). Donner, B., Niranjan, V. & Hoffmann, G. Safety of oseltamivir in pregnancy: a review of preclinical and clinical data. Drug Saf. 33, 631–642 (2010). Tanaka, T., Nakajima, K., Murashima, A., Garcia-Bournissen, F. & Koren, G. Safety of neuraminidase inhibitors against novel influenza A (H1N1) in pregnant and breasfeeding women. CMAJ 181, 55–58 (2009). Greer, L.G. et al. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet. Gynecol. 115, 711–716 (2010). Xie, H.Y. et al. Infant outcomes among pregnant women who used oseltamivir for treatment of influenza during the H1N1 epidemic. Am. J. Obstet. Gynecol. 208, 293.e1–7 (2013). Saito, S. et al. Outcomes of infants exposed to oseltamivir or zanamivir in utero during pandemic (H1N1) 2009. Am. J. Obstet. Gynecol. 209, 130.e1–9 (2013). Meijer, W.J. et al. Oseltamivir and its active metabolite cross the placenta at significant levels. Clin. Infect. Dis. 54, 1676–1677 (2012). Nanovskaya, T.N., Patrikeeva, S., Zhan, Y., Hankins, G.D. & Ahmed, M.S. Transplacental transfer of oseltamivir carboxylate. J. Matern. Fetal Neonatal. Med. 25, 2312–2315 (2012). McSharry, J.J., Weng, Q., Brown, A., Kulaway, R. & Drusano, G.L. Prediction of the pharmacodynamically linked variable of oseltamivir carboxylate for influenza A virus using an in vitro hollow-fiber infection model system. Antimicrob. Agents Chemother. 53, 2375–2381 (2009).
405
