Disposition of Carbamazepine and Phenytoin in Pregnancy

Tomson, Torbjörn; Lindbom, Ulla; Ekqvist, Britta; Sundqvist, Anders

doi:10.1111/j.1528-1157.1994.tb02922.x

Cited by 76 publications

(48 citation statements)

References 15 publications

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“…Hence the change in PHT Cpre-dose was used here to back calculate the magnitude of increase in CYP2C9 activity. In pregnant epileptic patients receiving a fixed PHT dose of 300 mg daily, PHT Cpre-dose is decreased by 43%, 51% and 61% during T1, T2 and T3, respectively [15,16]. Through sensitivity analysis, CYP2C9 fold-induction was 1.4-, 1.5-and 1.6-fold, during T1, T2 and T3, respectively, to recover the reported changes in PHT Cpre-dose ( Figure 4B).…”

Section: Figurementioning

confidence: 86%

“…The predicted PHT plasma unbound fraction was 15%, 26% and 30% during T1, T2 and T3, compared with the reported values of 14%, 16-38% and 26-40%, respectively [16,47].…”

Section: Figurementioning

confidence: 89%

“…(A) Predicted (solid line) and observed (symbols) [56][57][58] PHT plasma concentration-time profiles following chronic dosing of 300 mg day −1 (orally) in non-pregnant healthy subjects. (B) The grey bars represent predicted percent decrease in PHT trough concentration (Cpre-dose) and the white bars represent observed mean percent decrease in PHT Cpre-dose in pregnant women during pregnancy (T1, T2 and T3) vs. post-partum [16]. □, Lim et al [56]; ◊, Purkins et al [58]; •, Randinitis et al [57] …”

Section: Figurementioning

confidence: 99%

“…Maternal hepatic CYP2B6 was assumed to increase during pregnancy by 1.1-fold, 1.4-fold and 1.9-fold (based on in vitro to in vivo extrapolation, see results) during T1, T2 and T3, respectively. Maternal CYP2C9 activity was assumed to increase by 1.4-fold, 1.5-fold and 1.6-fold (reported by phenytoin PK) during T1, T2 and T3 [15,16] (see results). Maternal CYP2C19 activity, as reported by CLoral of the anti-malarial agent proguanil [17,18], was assumed to decrease by 62% and 68% during T2 and T3, respectively (see below).…”

Section: General Pregnancy Pbpk Model Structure and Key Assumptionsmentioning

confidence: 99%

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Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes, including CYP2B6, CYP2C9 and CYP2C19

Nallani

Zhao

et al. 2014

Br J Clin Pharmacol

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AIMConducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to predict the disposition in pregnant women of drugs cleared by multiple CYP enzymes. METHODSWe expanded and verified our previously published pregnancy PBPK model by incorporating hepatic CYP2B6 induction (based on in vitro data), CYP2C9 induction (based on phenytoin PK) and CYP2C19 suppression (based on proguanil PK), into the model. This model accounted for gestational age-dependent changes in maternal physiology and hepatic CYP3A, CYP1A2 and CYP2D6 activity. For verification, the pregnancy-related changes in the disposition of methadone (cleared by CYP2B6, 3A and 2C19) and glyburide (cleared by CYP3A, 2C9 and 2C19) were predicted. RESULTSPredicted mean post-partum to second trimester (PP : T2) ratios of methadone AUC, Cmax and Cmin were 1.9, 1.7 and 2.0, vs. observed values 2.0, 2.0 and 2.6, respectively. Predicted mean post-partum to third trimester (PP : T3) ratios of methadone AUC, Cmax and Cmin were 2.1, 2.0 and 2.4, vs. observed values 1.7, 1.7 and 1.8, respectively. Predicted PP : T3 ratios of glyburide AUC, Cmax and Cmin were 2.6, 2.2 and 7.0 vs. observed values 2.1, 2.2 and 3.2, respectively. CONCLUSIONSOur PBPK model integrating prior physiological knowledge, in vitro and in vivo data, allowed successful prediction of methadone and glyburide disposition during pregnancy. We propose this expanded PBPK model can be used to evaluate different dosing scenarios, during pregnancy, of drugs cleared by single or multiple CYP enzymes. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• During pregnancy, changes in physiology and absorption, distribution, metabolism and excretion (ADME) processes can significantly affect the disposition of drugs. Such changes may require adjustments in the dosing regimen of the drug.• Since conducting pharmacokinetic (PK) studies in pregnant women is challenging, alternative approaches that can predict adjustment of drug dosing regimens (if any) are highly desirable. WHAT THIS STUDY ADDS• We expanded and verified a physiologically based PK model, which incorporated gestational age-dependent changes in maternal physiology and major hepatic CYP enzyme activity, to predict disposition during pregnancy of drugs cleared by multiple CYP enzymes (e.g. glyburide and methadone).

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Section: Figurementioning

confidence: 86%

“…The predicted PHT plasma unbound fraction was 15%, 26% and 30% during T1, T2 and T3, compared with the reported values of 14%, 16-38% and 26-40%, respectively [16,47].…”

Section: Figurementioning

confidence: 89%

Section: Figurementioning

confidence: 99%

Section: General Pregnancy Pbpk Model Structure and Key Assumptionsmentioning

confidence: 99%

See 2 more Smart Citations

Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes, including CYP2B6, CYP2C9 and CYP2C19

Nallani

Zhao

et al. 2014

Br J Clin Pharmacol

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“…A prolonged period of titration and dosage adjustments may expose the fetus to abnormally high glucose concentrations and associated complications including macrosomia. Since pregnancy can accelerate the clearance of drugs [6][7], GLY plasma concentrations may be much lower during pregnancy (subnanogram/mL) and therefore the duration of action shorter than achieved in non-pregnant individuals. To study the pharmacokinetics of GLY during pregnancy and its maternal-fetal transfer, a highly sensitive and specific assay is needed that is capable of measuring subnanogram/mL plasma concentration of the drug.…”

Section: Introductionmentioning

confidence: 99%

Validation of a sensitive LC–MS assay for quantification of glyburide and its metabolite 4-transhydroxy glyburide in plasma and urine: An OPRU Network study

Kirby

Hébert

Easterling

et al. 2007

Journal of Chromatography B

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Glyburide (glibenclamide, INN), a second generation sulfonylurea is widely used in the treatment of gestational diabetes mellitus (GDM). None of the previously reported analytical methods provide adequate sensitivity for the expected sub-nanogram/mL maternal and umbilical cord plasma concentrations of glyburide during pregnancy. We developed and validated a sensitive and low sample volume liquid chromatographic-mass spectrometric (LC-MS) method for simultaneous determination of glyburide (GLY) and its metabolite, 4-transhydroxy glyburide (M1) in human plasma (0.5 ml) or urine (0.1 ml). The limits of quantitation (LOQ) for GLY and M1 in plasma were 0.25 and 0.40 ng/mL, respectively whereas it was 1.06 ng/mL for M1 in urine. As measured by quality control samples, precision (% coefficient of variation) of the assay was < 15% whereas the accuracy (% deviation from expected) ranged from −10.1-14.3%. We found that the GLY metabolite, M1 is excreted in the urine as the glucuronide-conjugate.

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