Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum period

Aida Kulo; Anne Smits; Sanita Maleškić; Marc van de Velde; Kristel van Calsteren; Jan de Hoon; Rene Verbesselt; Jan Deprest; Karel Allegaert

doi:10.17305/bjbms.2016.1515

Authors

Aida Kulo Center for Clinical Pharmacology, KU Leuven and University Hospitals Leuven, Leuven, Belgium; Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
Anne Smits Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium; Neonatal Intensive Care Unit, VU Medical Center, Amsterdam, The Netherlands,
Sanita Maleškić Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
Marc van de Velde Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Anaesthesiology, University Hospital Leuven, Leuven, Belgium
Kristel van Calsteren Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium,
Jan de Hoon Center for Clinical Pharmacology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
Rene Verbesselt Center for Clinical Pharmacology, KU Leuven and University Hospitals Leuven, Leuven, Belgium,
Jan Deprest Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium,
Karel Allegaert Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium; Department of Pediatric Surgery and Intensive Care, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

DOI:

https://doi.org/10.17305/bjbms.2016.1515

Keywords:

Pharmacokinetics, ketorolac, enantiomers, pregnancy, cesarean delivery, postpartum

Abstract

Racemic ketorolac clearance (CL) is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. The aim of this study was to investigate the effect of pregnancy and postpartum period on enantiomer-specific (S and R) intravenous (IV) ketorolac pharmacokinetics (PKs). Data in women shortly following cesarean delivery (n=39) were pooled with data in a subgroup of these women that was reevaluated in the later postpartum period (postpartum group, n=8/39) and with eight healthy female volunteers. All women received single IV bolus of 30 mg ketorolac tromethamine. Five plasma samples were collected at 1, 2, 4, 6, and 8 hours and plasma concentrations were determined using high performance liquid chromatography. Enantiomer-specific PKs were calculated using PKSolver. Unpaired analysis showed that distribution volume at steady state (V_ss, L/kg) for S- and R-ketorolac was significantly higher in women shortly following cesarean delivery (n=31) compared to postpartum group (n=8) or to healthy female volunteers (n=8). CL, CL to body weight, and CL to body surface area (CL/BSA) for S- and R-ketorolac were also significantly higher in women following delivery. In addition, S/R-ketorolac CL/BSA ratio was significantly higher at delivery. Paired PK analysis in eight women shortly following delivery and in postpartum group showed the same pattern. Finally, the simultaneous increase in CL and V_ss resulted in similar estimates for elimination half-life in both unpaired and paired analysis. In conclusion, pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance since S-ketorolac (analgesia) CL is even more increased compared to R-ketorolac CL, and S/R-ketorolac CL ratio is higher following delivery compared to postpartum period or to healthy female volunteers.

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Author Biographies

Aida Kulo, Center for Clinical Pharmacology, KU Leuven and University Hospitals Leuven, Leuven, Belgium; Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

Center for Clinical Pharmacology;
Department of Pharmacology
Anne Smits, Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium; Neonatal Intensive Care Unit, VU Medical Center, Amsterdam, The Netherlands,

Neonatal Intensive Care Unit
Sanita Maleškić, Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

Department of Pharmacology
Marc van de Velde, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium; Department of Anaesthesiology, University Hospital Leuven, Leuven, Belgium

Department of Cardiovascular Sciences;
Department of Anaesthesiology
Kristel van Calsteren, Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium,

Department of Obstetrics and Gynecology;
Department of Development and Regeneration
Jan de Hoon, Center for Clinical Pharmacology, KU Leuven and University Hospitals Leuven, Leuven, Belgium

Center for Clinical Pharmacology
Rene Verbesselt, Center for Clinical Pharmacology, KU Leuven and University Hospitals Leuven, Leuven, Belgium,

Center for Clinical Pharmacology
Jan Deprest, Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Leuven, Belgium,

Department of Obstetrics and Gynecology;
Department of Development and Regeneration
Karel Allegaert, Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium; Department of Pediatric Surgery and Intensive Care, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

Neonatal Intensive Care Unit;
Department of Pediatric Surgery and Intensive Care

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