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PP-21 Enantiomer-specific ketorolac pharmacokinetics in young women, including pregnancy and postpartum
  1. Maleskic Kapo1,
  2. Kulo1,
  3. Smits2,
  4. Van de Velde3,
  5. Van Calsteren4,
  6. De Hoon5,
  7. Verbesselt5,
  8. Deprest4,
  9. Allegaert2
  1. 1Medical Faculty University of Sarajevo, SARAJEVO, Bosnia-Herzegovina
  2. 2Neonatal Intensive Care Unit, University Hospitals Leuven, LEUVEN, Belgium
  3. 3Department of Cardiovascular Sciences, KU Leuven, LEUVEN, Belgium
  4. 4Department of Obstetrics and Gynaecology, University Hospitals Leuven, LEUVEN, Belgium
  5. 5Center for Clinical Pharmacology, KU Leuven and University Hospitals Leuven, LEUVEN, Belgium

Abstract

Background Ketorolac, a potent non-steroidal anti-in-flammatory drug, is a chiral substance. Racemic ketorolac clearance is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. We aimed to document the impact of pregnancy and postpartum on enantiomer-specific (S and R) ketorolac pharmacokinetics (PK) in young women.

Methods Observations shortly following caesarean de-livery (n=39) were pooled with data in subgroup of these women (n=8/39) four months afterwards (‘postpartum’) and with 8 healthy female volunteers, resulting in 47 un-paired and 8 paired PK estimates. All women received single intravenous bolus of ketorolac tromethamine (30 mg). Five (at 1, 2, 4, 6, 8 hour) plasma samples were collected and plasma concentrations were determined using HPLC method. Enantiomer-specific PKs were calculated using PKSolver.

Results Unpaired analysis documented that median distribution volume at steady state (Vss) for S-and R-ke-torolac was significantly higher in women following cae-sarean delivery (n=31) compared to postpartum (n=8) (S-ketorolac: 12.79 vs. 7.84 L, p=0.011; R-ketorolac: 8.96 vs. 5.86 L, p=0.001) or to healthy female volunteers (n=8).

(S-ketorolac: 12.79 vs. 9.14 L, p=0.002; R-ketorolac: 8.96 vs. 5.51 L, p<0.001). When corrected for BW, median Vss for both S-and R-ketorolac were significantly higher in women shortly following caesarean delivery compared to those in healthy female volunteers (S-ketorolac: 0.18 vs. 0.15 L/kg, p=0.037; R-ketorolac: 0.12 vs. 0.09 L/kg, p=0.001). The median clearance (CL) for S-and R-ketoro-lac was significantly higher in women following caesarean delivery compared to postpartum (S-ketorolac: 6.49 vs. 3.73 L/h, p<0.001; R-ketorolac: 2.14 vs. 1.43 L/h, p=0.002) or to healthy female volunteers (S-ketorolac: 6.49 vs. 3.60 L/h, p<0.001; R-ketorolac: 2.14 vs. 0.99 L/h, p=0.001). After taking the body size differences into account, CL to body weight (CL/BW) and CL to body surface area (CL/BSA) for S-and R-ketorolac were also higher following caesar-ean delivery compared to observations in postpartum (S-ketorolac:+33.3%, L/h·kg,+38.6%, L/h·m2; R-ketorolac:+33.3%, L/h·kg,+31.4%, L/h·m2) and in healthy female volunteers (S-ketorolac:+33.3%, L/h·kg,+48.4%, L/h·m2; R-ketorolac:+33.3%, L/h·kg,+56.8%, L/h·m2). In addition, S/R-ketorolac CL/BSA ratio was significantly higher at de-livery compared to postpartum (3.07 vs. 2.73, p=0.020). Paired PK analysis in 8 women following delivery or post-partum showed the same pattern. Finally, the simultane-ous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis.

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-ke-torolac CL and S/R-ketorolac CL ratio is higher following delivery compared to postpartum or to healthy female volunteers. For definitive physiological state-specific dos-ing recommendations in women, we encourage future repeated dosing pharmacokinetic studies in this specific population.

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