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Bosn J Basic Med Sci. 2017 February; 17(1): 54–60.
PMCID: PMC5341779

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

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 (Vss, 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 Vss 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.

KEY WORDS: Pharmacokinetics, ketorolac, enantiomers, pregnancy, cesarean delivery, postpartum

INTRODUCTION

Ketorolac is a potent nonsteroidal anti-inflammatory drug. It is a chiral substance consisting of S (−) and R (+) enantiomers. Although these ketorolac enantiomers come in equal portions [1], pharmacological activity, being almost exclusively attributed to S-ketorolac [2-6], makes enantiomer-specific ketorolac pharmacokinetics (PKs) clinically relevant.

Stereoselectivity has been described for ketorolac binding to plasma albumin as well as for ketorolac metabolism. Stereoselective binding to plasma albumin, which is lower for S- (98.4%) than for R-ketorolac (99.2%) [3], can explain enantiomer-specific PK differences [7,8]. In addition, stereoselective ketorolac metabolism by uridine-diphosphate-glucuronosyltransferase (UGT) 2B7 has been documented as higher for S- than for R-ketorolac [8,9]. As a consequence of those important stereoselective processes, a 4-5 fold higher distribution volume and clearance (CL) as well as twice shorter elimination half-life (2.5 versus 5 hours), have been documented for S- compared to R-ketorolac [10,11]. The S/R-ketorolac area under the curve (% AUC) after intravenous (IV) administration in adult patients is 0.36, independent of the administered dose [3].

Ketorolac is frequently used as analgesic drug in pregnancy and postpartum period [12-18]. Physiological changes during pregnancy and postpartum period (e.g., changes in total body water, plasma volume, plasma albumin levels, cardiac output, drug-metabolizing enzymes and drug transport, and kidney filtration) have been repeatedly shown to affect PKs of many drugs [19,20]. A higher free drug fraction in pregnancy is suggested to facilitate both the extraction in the liver and primary renal elimination [21]. Furthermore, the increase in in vivo phenotypic oxidation (CYP2C8-9) [8,9,22,23] and UGT2B7 activity during pregnancy [8,9], as well as different routes of drug elimination during pregnancy compared to those in the postpartum period and in healthy female volunteers, are also suggested [24].

Despite the frequent and off-label use of ketorolac in pregnancy and postpartum period [12-18], no data on the impact of pregnancy and postpartum period on enantiomer-specific ketorolac PK parameters are available. Therefore, the aim of our study was to investigate the effect of pregnancy and postpartum period on enantiomer-specific ketorolac PK parameters after a single IV ketorolac bolus.

MATERIALS AND METHODS

Ethics and study registration

The study was approved by the Ethics Committee of the University Hospitals, Leuven (internal study number 53048). Written informed consent was obtained from all women. The study was registered at ClinicalTrials.gov (NCT01291472, EudraCT 2011-000367-27).

Patients, ketorolac dosing, sample collection, and sample handling

Enantiomer-specific ketorolac PKs were calculated in women shortly following cesarean delivery (n = 39). A subgroup of these women (n = 8/39) was reevaluated in the later postpartum period. In addition, a cohort of healthy female volunteers was evaluated (n = 8).

An IV bolus of 30 mg ketorolac tromethamine (Taradyl®, Roche, Anderlecht, Belgium), equal to 20.345 mg of pure ketorolac (67%), was administered to all women. For women shortly following cesarean delivery, ketorolac was administered as part of multimodal analgesia at the University Hospitals Leuven, Belgium [24]. Except for the locoregional anesthetics and IV paracetamol administered as part of the multimodal analgesia following cesarean delivery, those women used no other medications for at least 48 hours before and during the study.

An IV bolus of 30 mg ketorolac tromethamine was administered as a single dose in the subgroup that was reevaluated in the postpartum period as well as in healthy female volunteers. Those women also used no other medications for at least 48 hours before and during the study.

To all women, ketorolac was administered as a slow injection over 30 seconds through a peripherally inserted venous cannula in the hand of the patient. Five blood samples (i.e., at 1, 2, 4, 6, and 8 hours post dose) were collected from a second peripheral venous cannula, dedicated only for study purposes. Blood samples were collected in lithium heparinized tubes, centrifuged, and plasma was stored at −20°C until analysis. Plasma concentrations of S- and R-ketorolac were determined using a validated high performance liquid chromatography analysis with UV detection after extraction procedure based on solid-phase extraction [25].

Pharmacokinetics

The main outcome measures were individual enantiomer-specific PK parameters. These were calculated using PKSolver, a program for PK and pharmacodynamic (PD) data analysis in Microsoft Excel [26]. We hereby assumed a noncompartmental model for IV bolus. AUC(0-∞), mg·h/L, elimination half-life (t1/2, h), distribution Vss, distribution Vss corrected for body weight (Vss/BW, L/kg), CL, CL corrected for BW (CL/BW, L/h·kg), and CL corrected for body surface area (CL/BSA, L/h·m2) were calculated, with BSA calculated by the following formula: BSA (m2) = 0.024265 body height (cm)0.3964 BW (kg)0.5378 [27]. To compare changes in CL between enantiomers, the ratio of S/R-ketorolac CL/BSA was also calculated and compared between the cohorts.

Statistics

Data were compared using the Kruskal–Wallis test for unpaired comparisons and the Wilcoxon signed-rank test for paired comparisons, and explored using Spearman’s rank correlation coefficient (MedCalc, Mariakerke, Belgium). A p < 0.05 was considered statistically significant. Results were reported by median and range.

RESULTS

A total of 47 women and 235 time-concentration profiles were included in this study.

PK estimates for S- and R-ketorolac in three groups

PK estimates in 31 women shortly following cesarean delivery were compared to the observations in eight women in the postpartum period (mean 21st, 17.1-22.6th postpartum week) and in eight healthy female volunteers (Table 1). The observed Cmax values for S- and R-ketorolac were significantly lower in the women shortly following cesarean delivery compared to the postpartum group and healthy female volunteers. As anticipated from the observed Cmax, the median Vss values for S- and R-ketorolac were significantly higher in the women shortly following cesarean delivery compared to the postpartum group and healthy female volunteers. When corrected for BW, the median Vss values for S- and R-ketorolac were significantly higher in the women shortly following cesarean delivery compared to the healthy female volunteers.

TABLE 1
Clinical data and PK estimates for S- and R-ketorolac (IV ketorolac single-dose) following cesarean delivery, in the postpartum period, and in healthy female volunteers

The median CL, CL/BW and CL/BSA values for S- and R-ketorolac were significantly higher in the women shortly following cesarean delivery compared to the postpartum group and healthy female volunteers (Figures (Figures11 and and22).

FIGURE 1
Unpaired comparison of (A) S-ketorolac clearance and (B) R-ketorolac clearance (CL) in women shortly following cesarean delivery versus postpartum group versus healthy female volunteers. The median CL values (L/h) for S- and R-ketorolac were significantly ...
FIGURE 2
Unpaired comparison of (A) S-ketorolac clearance corrected for body surface area (CL/BSA) and (B) R-ketorolac CL/BSA in women shortly following cesarean delivery versus postpartum group versus healthy female volunteers. The median CL/BSA (L/h·m ...

The ratio of S/R-ketorolac CL/BSA was significantly higher in the women shortly following cesarean delivery compared to the postpartum group (Figure 3).

FIGURE 3
Unpaired comparison of the ratio of S and R-ketorolac clearance corrected for body surface area (S/R-ketorolac CL/BSA ratio), in women shortly following cesarean delivery versus postpartum group versus healthy female volunteers. The ratio was significantly ...

No difference in the median elimination half-life was documented between the three groups (Table 1).

Paired analysis of PK estimates in women shortly following cesarean delivery and in postpartum period

For the same women (n = 8) the PK estimates observed shortly following cesarean delivery and those obtained in the postpartum period (mean 21st, 17.1-22.6th postpartum week), were compared (Table 2). The observed Cmax values for S- and R-ketorolac were significantly lower shortly following cesarean delivery compared to the postpartum period.

TABLE 2
Clinical data and PK estimates for S- and R-ketorolac (IV ketorolac single-dose) in the same group of women (n=8) in two different periods

No differences either in Vss or Vss/BW were found for S-ketorolac while median Vss for R-ketorolac was significantly higher shortly following cesarean delivery compared to the postpartum period of the same women.

The CL and CL/BSA values for S- and R-ketorolac were significantly higher shortly following cesarean delivery compared to the postpartum period of the same women. In addition, for S-ketorolac, the median CL/BW value was also significantly higher shortly following cesarean delivery compared to the postpartum period.

The ratio of S/R-ketorolac CL/BSA was not different between shortly following cesarean delivery and postpartum periods of the same women. No difference in the median elimination half-life was documented between these two physiological states of the same women (Table 2).

DISCUSSION

To the best of our knowledge, this study is the first report on the impact of pregnancy and postpartum period on enantiomer-specific PKs of IV ketorolac. Significant differences in median PK estimates in the women shortly following cesarean delivery were observed compared to the postpartum group and healthy female volunteers.

As anticipated, higher BW and BSA values were observed in the women shortly following cesarean delivery compared to the postpartum group (Table 1). However, even after taking the body size differences into account, the CL values of S- and R-ketorolac were shown to be higher in the women shortly following cesarean delivery compared to the observations in the postpartum group (mean 21st week) (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, +40.6%, L/h·m2; R-ketorolac: +33.3%, L/h·kg, +50.0%, L/h·m2) (Table 1 and Figure 2).

The ratio of S/R-ketorolac CL/BSA reflects the difference in changes of the enantiomer-specific CLs (S or R). Interestingly, S/R-ketorolac CL/BSA was significantly higher in the women shortly following cesarean delivery compared to the postpartum group (Figure 3). As mentioned earlier, enantiomer-specific PK differences may be explained by stereoselective binding of ketorolac to plasma albumin [7,8]. Lower albumin binding for S- than for R-ketorolac [3], with additional lower protein binding due to pregnancy induced hypoalbuminemia [8,9,28], results in even higher free concentrations of S- compared to R-ketorolac. This, at least in part, may explain the impact of pregnancy on the S/R-ketorolac ratio.

The impact of pregnancy on the S/R-ketorolac ratio is of PD relevance, since this means that S-CL is somewhat more increased compared to R-CL, in women shortly following cesarean delivery. Since the analgesic effect of ketorolac relates exclusively to S-ketorolac, it is reasonable to assume that analgesia will disappear earlier shortly following cesarean delivery compared to the postpartum period.

The additional paired PK analysis in the eight women following cesarean delivery and in their later postpartum period confirmed this pattern. Finally, the simultaneous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis.

As for other analgesics, a single dose of ketorolac can be applied, making Cmax a relevant parameter for determining the therapeutic effect [29]. As anticipated from our results, increased ketorolac Vss in the women shortly following cesarean delivery resulted in Cmax to be significantly lower compared to the postpartum group (−40.0% for S-ketorolac and −36.2% for R-ketorolac), as well as compared to the healthy female volunteers (−43.2% for S-ketorolac and −44.4% for R-ketorolac).

The current enantiomer-specific PKs confirm previously reported effect of physiological changes in pregnancy and postpartum period on racemic ketorolac PKs [21,23,30,31]. Distribution volume of racemic ketorolac was 40% and CL was 50% higher in post-cesarean women compared to healthy female volunteers [21]. This was also confirmed by paired analysis which showed distribution volume of racemic ketorolac in post-cesarean women to increase 40-50% and total CL to increase 30-40% compared to those results in 4-5 months postpartum of the same women [21].

Compared to non-pregnant women, pregnant women have lower protein binding as well as a higher fractional volume of body water [8,9,28]. In addition, a 3-7% decrease in plasma protein binding was documented to double distribution volume of ketorolac [32]. Having in mind that ketorolac is also a low-extraction drug [2,32], its hepatic CL [33] is directly proportional to its unbound fraction in plasma [34]. This likely explains the higher CL and distribution volume for racemic ketorolac [30,31] and both ketorolac enantiomers in women shortly following cesarean delivery compared to group in postpartum period and in healthy female volunteers. Proportional change in CL and distribution volume results in no change in ketorolac half-life, as documented in this study.

The same pattern of CL and distribution volume, in which these values are higher for pharmacologically active S- compared to R-ketorolac [10,11], was documented after IV ketorolac administration in children [8,10,11] and after all ketorolac administration routes in non-pregnant women and men [3,35]. These results are also confirmed in each cohort of the current study (Table 3). S-ketorolac CL [6,33] and distribution volume [11] are also shown to be age-dependent (i.e., higher in children compared to adults). The age range in our study was limited to young adulthood (25-44 years).

TABLE 3
Clinical data, IV dose administered, and CL and distribution volume (Vd) estimates for S- and R-ketorolac in different studies

This study certainly has some limitations. First, due to the vulnerability of the postpartum period, the sample size of those women was limited. Nevertheless, we were still able to perform reliable paired analysis. Second, according to some authors, the analysis of only 8-hour time course might cause an underestimation of the true half-life [2]. However, the 8-hour time interval in our study was initially based on the clinical practice of post cesarean delivery ketorolac administration (q8h) in our hospital [31]. In addition, this study showed the 8-hour interval to represent a minimum of 2 half-life values for R-ketorolac and a minimum of 3-4 half-life values for S-ketorolac in all cohorts that were evaluated.

The fact that only one of the ketorolac enantiomers has analgesic effects makes enantiomer-specific PKs of clinical relevance and illustrates the need to explore the enantiomer-specific PK/PD relation. In addition, taking into account other factors that can influence the PDs, we suggest reconsidering the current dosing regimens. This means that, due to PK changes during pregnancy, extrapolation of dosing regimens from the results obtained in adult women should be performed with caution. Accordingly, because of the higher distribution volume, an initial loading dose is suggested in women following delivery, to achieve therapeutic plasma concentrations. Furthermore, the BW-adjusted maintenance doses of ketorolac could be higher in women following delivery compared to postpartum and non-pregnant/non-postpartum women, and could be applied with higher intermittent dosing or more frequent administration.

Documented PK differences and quite extensive enantiomer-specific ketorolac PK variability among young women illustrate the relevance to perform PK studies in different states of adult women’s life and confirm our earlier observations on IV paracetamol [36]. For definitive physiological state-specific dosing recommendations in women, we encourage future repeated dosing PK studies in this specific population.

CONCLUSION

Pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance, since S-ketorolac (analgesia) CL is higher in women shortly following cesarean delivery compared to postpartum group and healthy female volunteers, and this increase is even higher for S-CL compared to R-CL (S/R CL ratio).

DECLARATION OF INTERESTS

The authors declare no conflict of interests.

ACKNOWLEDGMENTS

The clinical research of Karel Allegaert was supported by a Fundamental Clinical Investigatorship (1800214 N). Aida Kulo was supported by a JoinEU-SEE (2010-2012) and Eraweb (2015/16) scholarship. The clinical research was in part supported by an unrestricted research grant provided by the Belgian Society for Anesthesia and Resuscitation.

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