Body weight, gender and pregnancy affect enantiomer‐specific ketorolac pharmacokinetics

Abstract

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.

Impact of enantiomer‐specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis

“…This is important as previous studies identified changes in the enantiomer-specific ketorolac pharmacokinetics (PK) in various populations separately, such as in infants, toddlers, healthy adults and women at delivery or postpartum. [11][12][13][14][15] These studies showed significant differences in PK parameters between the S-and R-enantiomer, both within and between these populations. To account for population based PK differences, paediatric dosage regimens have been derived that yield the same racemic exposure as in adults.…”

“…In total, 5 study groups contributed data for this pooled analysis. [11][12][13][14][15] A total of 80 subjects were included: infants (n = 33, median age 0.83, interquartile range 0.56-1.03 years), children (n = 2, 8 and 14 years), adults (n = 45, median age 30, interquartile range 26-36 years). A total of 1020 plasma concentrations for S-and R-ketorolac were available (Figure 1).…”

“…Furthermore, the PK parameters obtained from the final PK model of both S-and R-ketorolac confirm that significant differences exist between populations and between enantiomers, driven by allometry-based changes in the parameters. [11][12][13][14][15] By use of a simulation-based modelling approach, the contribution of S-ketorolac to the racemic concentration was investigated, which showed clear differences in the reached S-ketorolac concentrations and the time above the EC 50 in both populations. This study further illustrates that a EC 50-racemic of 0.37 mg/L should be used with caution for the optimization of dosage regimens in infants and targeting a higher EC 50-racemic or using a target S-ketorolac concentration should be performed.…”

“…To account for population based PK differences, paediatric dosage regimens have been derived that yield the same racemic exposure as in adults. 16 However, due to the effect of maturation and allometry-based changes in the PK for the 2 enantiomers, the same racemic concentration may yield differences in the enantiomer-specific concentrations compared to adults, [11][12][13][14][15] hence a lower/higher S-ketorolac concentration may be obtained with equal racemic concentrations. Since S-ketorolac is solely driving the analgesic effects, more information needs to be obtained on the contribution of S-ketorolac in these populations to assess if population-specific target EC 50-racemic and/or dose adaptions are needed.…”

Levosalbutamol as alternative to drugs on the basis of racemic salbutamol: Review of the results of pre-clinical research

“…Аминокислоты, за исключением глицина, характеризуются хиральными свойствами, в связи с чем активные сайты связывания в составе протеинов являются асимметричными, а значит, помимо комлементарности, важным условием эффективного взаимодействия с лигандом, обладающим хиральными свойствами, является пространственная конфигурация его энантиомеров. Последняя, в свою очередь, определяет существенные различия аффинитета связывания R-и S-энантиомеров хиральных лекарственных субстанций (Burke and Henderson, 2002;Kubinyi, 2003) и лежит в основе феномена энантиоселективности их фармакокинетики или фармакодинамики (Barnette et al, 2017;Kuchay and Mithal, 2017;Noguchi et al, 2017;Välitalo et al, 2017). Удаление из лекарственного препарата энантиомера, лишенного фармакологической активности или обладающего неоптимальными фармакодинамическими или фармакокинетическими свойствами, может ассоциироваться с повышением клинической эффективности лекарственных средств, в том числе ранее одобренных для клинического применения, минимизировать фармакодинамическую и фармакокинетическую вариабельность ответов на лечение и, возможно, снизить вероятность развития нежелатель-ных событий, ассоциированных с фармакотерапией рацематами.…”