Influence of Gestational Age and Body Weight on the Pharmacokinetics of Labetalol in Pregnancy

Abstract

Background and Objectives Labetalol is frequently prescribed for treatment of hypertension during pregnancy. However, the influence of pregnancy on labetalol pharmacokinetics is uncertain, with inconsistent findings reported by previous studies. This study examined the population pharmacokinetics of oral labetalol during and after pregnancy in women receiving labetalol for hypertension. Methods Data were collected from 57 women receiving the drug for hypertension from the 12th week of pregnancy through 12 weeks postpartum using a prospective, longitudinal design. A sparse sampling strategy guided collection of plasma samples. Samples were assayed for labetalol by high performance liquid chromatography. Estimation of population pharmacokinetic parameters and covariate effects was performed by nonlinear mixed effects modeling using NONMEM. Final population model was validated by bootstrap analysis and visual predictive check. Simulations were performed with the final model to evaluate the appropriate body weight to guide labetalol dosing. Results Lean body weight (LBW) and gestational age, i.e., weeks of pregnancy, were identified as significantly influencing oral clearance (CL/F) of labetalol, with CL/F ranging from 1.4-fold greater than postpartum values at 12 weeks gestational age to 1.6-fold greater at 40 weeks. Doses adjusted for LBW provide more consistent drug exposure than doses adjusted for total body weight. The apparent volumes of distribution for the central compartment and at steady-state were 1.9-fold higher during pregnancy. Conclusions Gestational age and LBW impact the pharmacokinetics of labetalol during pregnancy and have clinical implications for adjusting labetalol doses in these women.

PK/PD Modeling of β-Blockers in Cardiovascular Disease: An Update

“…Saotome et al [54] have described the relationship between labetalol plasma levels and the hypotensive response was described in pregnant women with moderate-to-severe hypertension during the third trimester by using a sigmoidal E max model. The authors found a three-to fivefold intersubject variability in the PD parameters E max and EC 50 of labetalol hypotensive response, demonstrating the relevance of PK/PD studies for the evaluation of the variability in antihypertensive drug response and optimization of dose selection [62].…”

Is personalized medicine achievable in obstetrics?

“…A recent study found that gestational age and lean body weight were significantly associated with oral clearance 25 . Labetalol is cleared predominantly by glucuronidation through UGT1A1 and UGT2B7 26 .…”

What is the evidence for using labetalol as a first-line treatment option for hypertension in pregnancy?

“…It has a short half-life (4 to 6 hours), requiring dosing to be split to two to three times per day, which can contribute to difficulties with adherence. A study that examined the impact of gestation on the pharmacokinetics of labetalol found a significant increase in the oral clearance rate across gestation and when compared with the oral clearance rate outside pregnancy, which might explain the findings of a recent mechanistic study that showed that pregnant women prescribed labetalol, compared with nifedipine, had greater variation in blood pressure over 24 hours 14,15. Possible adverse effects include lethargy, weakness and somnolence, and it is relatively contraindicated in women with asthma as it can cause bronchospasm.Labetalol is the only antihypertensive agent that holds a Medicines and Healthcare Regulatory Agency licence for use in pregnancy, but this is primarily a reflection of the difficulties and apathy surrounding licensing drugs for use in pregnancy.…”