Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

Pariente, Gali; Leibson, Tom; Carls, Alexandra; Adams‐Webber, Thomasin; Itô, Shinya; Koren, Gideon

doi:10.1371/journal.pmed.1002160

Cited by 233 publications

(205 citation statements)

References 236 publications

(115 reference statements)

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“…Quetiapine is metabolized mainly by CYP3A4,13 an enzyme known to be induced during pregnancy 4, 5, 6, 7. Similar drug concentration declines in pregnancy have also been reported for other CYP3A4 substrates,14, 15 and also in a previous case report for quetiapine 8.…”

Section: Discussionsupporting

confidence: 77%

“…A myriad of physiological changes may occur during pregnancy and alter drug disposition 4, 5, 6, 7. Changes in volume of distribution may alter the concentration after the first dose and the loading dose requirements, and alter peak concentrations and elimination half‐life,6 but generally have little influence on the trough concentration at steady state.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous physiological changes occur during pregnancy, some of which may cause changes in drug disposition, e.g., due to alterations in body weight, plasma volume, hepatic metabolic capacity, and renal function 4, 5, 6, 7. Thus, the right drug dose for a woman prior to conception or for the patient group in general is not necessarily the right dose during pregnancy.…”

mentioning

confidence: 99%

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Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Westin

Brekke

Molden

et al. 2017

Clin Pharma and Therapeutics

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Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (−76%; confidence interval (CI), −83%, −66%; P < 0.001) and aripiprazole (−52%; CI, −62%, −39%; P < 0.001), but not for olanzapine (−9%; CI, −28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Westin

Brekke

Molden

et al. 2017

Clin Pharma and Therapeutics

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“…This may be an overestimate because oral bioavailability of morphine and M6G in an adult is 30% and 10%, respectively, but data in the neonatal period are lacking. In addition, it is important to note that these findings are based on the first 2 days postpartum, which are likely to be characterized by high morphine‐to‐M6G clearance due to pregnancy‐associated induction of UGT2B7 …”

Section: Opioid Use In Breastfeedingmentioning

confidence: 99%

Opioids in Breast Milk: Pharmacokinetic Principles and Clinical Implications

Itô

2018

The Journal of Clinical Pharma

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Safety of maternal drug therapy during breastfeeding may be assessed from estimated levels of drug exposure of the infant through milk. Pharmacokinetic (PK) principles predict that the lower the clearance is, the higher the infant dose via milk will be. Drugs with low clearance (<1 mL/[kg·min]) are likely to cause an infant exposure level greater than 10% of the weight‐adjusted maternal dose even if the milk‐to‐plasma concentration ratio is 1. Most drugs cause relatively low‐level exposure below 10% of the weight‐adjusted maternal dose, but opioids require caution because of their potential for severe adverse effects. Furthermore, substantial individual variations of drug clearance exist in both mother and infant, potentially causing drug accumulation over time in some infants even if an estimated dose of the drug through milk is small. Such PK differences among individuals are known not only for codeine and tramadol through pharmacogenetic variants of CYP2D6 but also for non‐CYP2D6 substrate opioids including oxycodone, indicating difficulties of eliminating PK uncertainty by simply replacing an opioid with another. Overall, opioid use for pain management during labor and delivery and subsequent short‐term use for 2‐3 days are compatible with breastfeeding. In contrast, newly initiated and prolonged maternal opioid therapy must follow a close monitoring program of the opioid‐naive infants. Until more safety data become available, treatment duration of newly initiated opioids in the postpartum period should be limited to 2‐3 days in unsupervised outpatient settings. Opioid addiction treatment with methadone and buprenorphine during pregnancy may continue into breastfeeding, but infant conditions must be monitored.

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“…Pregnancy involves substantial physiological changes, including delayed gastric emptying, increased cardiac output, and increased glomerular ﬁltration rate (Pariente et al, ). In addition, elevated hormones, especially oestradiol (E2) and progesterone (P4), probably regulate the expression of drug transporters, and thereby affect the distribution of drugs (Isoherranen & Thummel, ).…”

Section: Introductionmentioning

confidence: 99%

Roles of organic anion transporter 2 and equilibrative nucleoside transporter 1 in hepatic disposition and antiviral activity of entecavir during non‐pregnancy and pregnancy

Sun

et al. 2019

British J Pharmacology

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Background and Purpose Entecavir (ETV), a first‐line antiviral drug against hepatitis B virus (HBV), has the possibility to be used to prevent mother‐to‐child transmission. The aim of present study was to clarify the mechanism of ETV uptake into hepatocytes and evaluate the alteration of ETV's hepatic distribution during pregnancy. Experimental Approach The roles of equilibrative nucleotide transporter (ENT) 1 and organic anion transporter (OAT) 2 in ETV accumulation and anti‐HBV efficacy were studied in human ENT1 or OAT2 overexpressed cell models and HepG2.2.15 cells, respectively; meanwhile, the liver‐to‐plasma ETV concentration ratios in non‐pregnant and pregnant mice were measured to evaluate the effect of pregnancy on ETV hepatic distribution. Key Results ETV was shown to be a substrate of ENT1 and OAT2. An ENT1 inhibitor significantly decreased the efficacy of ETV in HepG2.2.15 cells, while overexpression of OAT2 increased susceptibility of HBV to ETV. The liver‐to‐plasma ETV concentration ratios in pregnant mice were sharply reduced; whereas, the absolute concentration of ETV in the liver did not obviously alter in pregnancy. Although oestradiol and progesterone showed a concentration‐dependent inhibition on ETV accumulation both in hepatic cell lines and in primary human hepatocytes, a physiologically relevant concentration of oestradiol and progesterone did not affect antiviral activity of ETV. Conclusions and Implications OAT2 and ENT1 are the main transporters involved in the hepatic uptake and anti‐HBV efficacy of ETV. The concentration of ETV in the liver was not obviously altered during pregnancy, which indicates that dosage adjustment in pregnancy is not necessary.

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Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

Cited by 233 publications

References 236 publications

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition

Opioids in Breast Milk: Pharmacokinetic Principles and Clinical Implications

Roles of organic anion transporter 2 and equilibrative nucleoside transporter 1 in hepatic disposition and antiviral activity of entecavir during non‐pregnancy and pregnancy

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