Ondansetron Pharmacokinetics in Pregnant Women and Neonates: Towards a New Treatment for Neonatal Abstinence Syndrome

Elkomy, Mohammed H.; Sultan, Pervez; Carvalho, Brendan; Peltz, Gary; Wu, Marion L.; Clavijo, Claudia F.; Galinkin, Jeffrey L.; Drover, David R.

doi:10.1002/cpt.5

Cited by 27 publications

(25 citation statements)

References 28 publications

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“…A 5-HT antagonist, ondansetron, recently entered clinical trials for the prevention of NAS symptoms when delivered maternally shortly before birth and continuing in the postnatal period (Elkomy et al, 2015; https://clinicaltrials.gov/ct2/show/ NCT01965704). However, this treatment, although designed An Opioid Antagonist-Based Preventive Therapy for NAS to reduce the length of stay in the intensive care unit, would not be expected to prevent the occurrence of dependence and any related developmental consequences.…”

Section: Discussionmentioning

confidence: 99%

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

Oberdick

Ling

Phelps

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Prolonged fetal exposure to opioids results in neonatal abstinence syndrome (NAS), a major medical problem requiring intensive care and increased hospitalization times for newborns with NAS. Multiple strategies are currently available to alleviate withdrawal in infants with NAS. To prevent NAS caused by opioid maintenance programs in pregnant women, blocking fetal dependence without compromising the mother's opiate therapy is desirable. Here we tested in pregnant mice whether a peripherally selective opioid antagonist can preferentially enter the fetal brain and, thereby, in principle, selectively protect the fetus. We show using mass spectrometry that 6b-naltrexol, a neutral opioid antagonist with very limited ability to cross the bloodbrain barrier (BBB), readily crosses the placental barrier and enters the fetal brain at high levels, although it is relatively excluded from the maternal brain. Furthermore, owing to the late development of the BBB in postnatal mice, we show that 6b-naltrexol can readily enter the juvenile mouse brain until at least postnatal day 14. Taking advantage of this observation, we show that long-term exposure to morphine starting in the second postnatal week causes robust and quantifiable dependence behaviors that are suppressed by concomitant administration of 6b-naltrexol with much greater potency (ID 50 0.022-0.044 mg/kg, or 1/500 the applied dose of morphine) than previously demonstrated for either the suppression of central nervous system opioid effects or the induction of withdrawal in adults. These results indicate that peripherally selective opioid antagonists capable of penetrating the placenta may be beneficial for preventing or reducing neonatal dependence and NAS in a dose range that should not interfere with maternal opioid maintenance.

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Section: Discussionmentioning

confidence: 99%

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

Oberdick

Ling

Phelps

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Clinical data for the investigated drugs herein were taken from the literature (18,(39)(40)(41)(42)(43)(44)(45)(46)(47) and are listed for each drug in Table 3. Blood samples were obtained from maternal peripheral venous blood and umbilical vein blood plasma at delivery.…”

Section: Clinical Datamentioning

confidence: 99%

Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

et al. 2021

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Background: While physiologically based pharmacokinetic (PBPK) models generally predict pharmacokinetics in pregnant women successfully, the confidence in predicting fetal pharmacokinetics is limited because many parameters affecting placental drug transfer have not been mechanistically accounted for.Objectives: The objectives of this study were to implement different maternal and fetal unbound drug fractions in a PBPK framework; to predict fetal pharmacokinetics of eight drugs in the third trimester; and to quantitatively investigate how alterations in various model parameters affect predicted fetal pharmacokinetics.Methods: The ordinary differential equations of previously developed pregnancy PBPK models for eight drugs (acyclovir, cefuroxime, diazepam, dolutegravir, emtricitabine, metronidazole, ondansetron, and raltegravir) were amended to account for different unbound drug fractions in mother and fetus. Local sensitivity analyses were conducted for various parameters relevant to placental drug transfer, including influx/efflux transfer clearances across the apical and basolateral membrane of the trophoblasts.Results: For the highly-protein bound drugs diazepam, dolutegravir and ondansetron, the lower fraction unbound in the fetus vs. mother affected predicted pharmacokinetics in the umbilical vein by ≥10%. Metronidazole displayed blood flow-limited distribution across the placenta. For all drugs, umbilical vein concentrations were highly sensitive to changes in the apical influx/efflux transfer clearance ratio. Additionally, transfer clearance across the basolateral membrane was a critical parameter for cefuroxime and ondansetron.Conclusion: In healthy pregnancies, differential protein binding characteristics in mother and fetus give rise to minor differences in maternal-fetal drug exposure. Further studies are needed to differentiate passive and active transfer processes across the apical and basolateral trophoblast membrane.

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“…11 Ondansetron is also prescribed to prevent neonatal abstinence syndrome. 12 Therapeutic Index, Toxicity, and Contraindications…”

Section: Therapeutic Indicationsmentioning

confidence: 99%

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron

Rajawat

Belubbi

Nagarsenker

et al. 2019

Journal of Pharmaceutical Sciences

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Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT 3 receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of "high solubility" as well as "high permeability" and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran ® 8 mg) and multiples thereof (16 mg ¼ Zofran ® 8 mg Â 2 tablets and 24 mg ¼ Zofran ® 8 mg Â 3 tablets) meet the criteria of "rapidly dissolving" in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.

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Ondansetron Pharmacokinetics in Pregnant Women and Neonates: Towards a New Treatment for Neonatal Abstinence Syndrome

Cited by 27 publications

References 28 publications

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice

Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron

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