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Body weight, gender and pregnancy affect enantiomer‐specific ketorolac pharmacokinetics
Author(s) -
Välitalo Pyry A.,
Kemppainen Heidi,
Kulo Aida,
Smits Anne,
Calsteren Kristel,
Olkkola Klaus T.,
Hoon Jan,
Knibbe Catherijne A. J.,
Allegaert Karel
Publication year - 2017
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13311
Subject(s) - ketorolac , pharmacokinetics , medicine , ketorolac tromethamine , confidence interval , volume of distribution , pregnancy , body mass index , anesthesia , analgesic , genetics , biology
Aims Although ketorolac analgesia is linked only to the S‐enantiomer, there is limited information on the stereo‐selective pharmacokinetics of this agent. We studied the stereo‐selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4–5 months postpartum, and males and nonpregnant females. Methods Nonlinear mixed‐effect modelling was used to evaluate the stereo‐selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery ( n = 41), 4–5 months postpartum ( n = 8, paired), and in male ( n = 12) and nonpregnant female ( n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. Results For both the R‐ and S‐enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. Conclusions Besides the anticipated impact of body weight on clearance, R‐ and S‐ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.