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DRUG METABOLISM |
From Merck Research Laboratories, West Point, Pennsylvania (Mr. Shadle, Dr. Lee, Dr. Majumdar, Dr. Petty, Ms. Gargano, Dr. Bradstreet, Dr. Evans) and Buffalo Clinical Research Center, Buffalo, New York (Dr. Blum).
Address for reprints: Craig Shadle, Clinical Pharmacology, Merck Research Laboratories, BLB-33, 5 Sentry Parkway West, Blue Bell, PA 19422.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Aprepitant • midazolam • tolbutamide • CYP3A4 • CYP2C9 • pharmacokinetics
Previous clinical drug interaction studies with aprepitant suggested that it influences CYP3A4 and CYP2C9 activity. Results of a study using oral midazolam as a probe found that dosing with aprepitant 125 mg p.o. on day 1, followed by 80 mg p.o. per day on days 2 through 5, had a moderate inhibitory effect on CYP3A4 activity, manifested as 2.3- and 3.3-fold increases in midazolam plasma AUC on days 1 and 5, respectively.5 Moreover, data from studies in which aprepitant was administered once daily for 4 to 8 weeks showed that the aprepitant plasma concentration increased over the first week to a peak around day 7 (AUC0-24 h approximately 2- to 3-fold higher on day 7 vs. day 1), then gradually declined over 21 to 35 days to steady state, at which the AUC0-24 h was approximately 1- to 1.5-fold higher than on day 1 (data on file). Since aprepitant is also metabolized by CYP3A4, these patterns are consistent with possible autoinduction of CYP3A4 activity by aprepitant. Inhibition of CYP3A4 predominates at times when aprepitant is present. However, if aprepitant induces CYP3A4, it is possible that it would produce a net inductive effect on CYP3A4 in the period immediately following completion of aprepitant dosing, when aprepitant plasma concentrations disappear. If such an inductive effect persists at the time of subsequent cycles of chemotherapy, there is a potential for increased clearance (and potentially decreased efficacy) of CYP3A4-dependent chemotherapy agents (e.g., taxanes, vinca alkaloids, epipodophyllotoxins, ifosfamide, and irinotecan) if they were to be administered soon after completion of aprepitant dosing.
The potential for the aprepitant regimen for CINV to produce net induction of CYP3A4 activity was assessed in the present study using i.v. midazolam, a sensitive probe substrate. Midazolam itself does not significantly inhibit any CYPs, making interaction with concomitantly administered drugs unlikely. Since most chemotherapeutic agents are administered intravenously, i.v. midazolam was appropriate to assess the potential effect of aprepitant on parenterally administered chemotherapy agents metabolized by CYP3A4. The potential for aprepitant to induce CYP3A4 activity was assessed on day 4 (i.e., during the interval 24-48 h after the last dose of aprepitant) and at time points following completion of dosing of the aprepitant CINV regimen at which subsequent cycles of chemotherapy might be initiated (e.g., days 8 and 15 relative to day 1 of the first cycle).
In addition to assessing potential effects on CYP3A4 over 2 weeks, the effect of aprepitant on CYP2C9 was also characterized in this study using oral tolbutamide as a CYP2C9 probe drug.6 In an earlier study, an apparent inductive effect of aprepitant on CYP2C9 was suggested by a decrease in S(-)-warfarin plasma concentrations with concomitant aprepitant, a decrease that persisted for several days beyond cessation of aprepitant dosing.7 Although few if any chemotherapeutic agents are thought to be metabolized predominantly by CYP2C9, it was of interest to characterize the time course of CYP2C9 induction to assess the magnitude and duration of potential effects of the aprepitant regimen on narrow therapeutic index drugs that are CYP2C9 substrates (e.g., warfarin) that might be coadministered to patients receiving chemotherapy.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Because three distinct polymorphisms of the CYP2C9 gene have been identified, genotyping for CYP2C9 was performed for all subjects in this study, and the tolbutamide pharmacokinetic data were evaluated to determine whether induction of CYP2C9 activity by aprepitant differed between subjects who were or were not homozygous for the wild-type CYP2C9 allele.
Design
In this double-blind, placebo-controlled study, subjects were randomized (12 subjects per group) to one of two treatment groups: group 1 received a 3-day regimen of aprepitant (125 mg p.o. on day 1 and 80 mg p.o. on days 2 and 3); group 2 received matching placebo. In addition, subjects in both groups received open-label administration of the probe drugs—midazolam 2-mg i.v. infused over 2 minutes and tolbutamide 500 mg p.o.—at baseline (days -7 to -5) and on days 4, 8, and 15 relative to initiation of aprepitant dosing on day 1. The oral drugs were given with 240 mL of water. All drugs were given in the morning, 30 minutes after a light breakfast. Subjects were given a light snack and orange juice approximately 2 hours after dosing.
Blood for measurement of plasma aprepitant concentrations was drawn from each subject at baseline and predose on days 2, 3, and 4 as trough samples. The plasma concentration profile of midazolam was measured in all subjects over 0 to 24 hours following midazolam at baseline (days -5 to -7) and starting on days 4, 8, and 15. Plasma concentrations of tolbutamide were measured over 0 to 48 hours following tolbutamide administration at baseline and starting on study days 4, 8, and 15. Subjects remained in the clinical research unit for 48 hours after probe drugs were administered. Tolerability was assessed by prestudy and poststudy physical examinations, including vital signs, a 12-lead electrocardiogram, and laboratory tests, as well as any adverse events. Vital signs and blood glucose levels were also monitored at specified time points. Any adverse experiences were rated by the investigator as to seriousness (according to a regulatory definition), relatedness to study drug, and severity.
Pharmacokinetic Methods
Plasma samples collected for the aprepitant assay were analyzed for aprepitant by the Department of Drug Metabolism, West Point, Merck Research Laboratories. The analytical method used liquid-liquid extraction for analyte isolation followed by detection and quantification of analyte using liquid chromatography/tandem mass spectrometry. The lower limit of quantification (LOQ) was 10 ng/mL. Plasma and urine samples collected for midazolam and tolbutamide and metabolite assays were analyzed by PPD Development (Richmond, VA) using liquid chromatography/tandem mass spectrometry. The LOQ for midazolam in plasma was 0.1 ng/mL. The LOQ for tolbutamide in plasma was 0.1 µg/mL. The LOQ for tolbutamide, hydroxytolbutamide, and carboxytolbutamide in urine was 5 ng/mL, 0.3 µg/mL, and 0.6 µg/mL, respectively.
The following pharmacokinetic parameters were evaluated for plasma midazolam and tolbutamide: area under the plasma concentration-time curve from time 0 to time infinity (AUC0-
), peak plasma concentration (Cmax) and corresponding time of occurrence (tmax), and apparent terminal half-life (t1/2). Plasma clearance (CLp) was estimated for midazolam, and urinary excretion over 48 hours (Ue0-48, percentage of dose) was calculated for the metabolites of tolbutamide (carboxytolbutamide and hydroxytolbutamide). AUC0-, Cmax, tmax, t1/2, and CLp were analyzed by noncompartmental modeling using WinNonlin software. Amounts of carboxytolbutamide and hydroxytolbutamide excreted in urine were calculated by multiplying urinary carboxytolbutamide and hydroxytolbutamide concentrations by urine volume voided in the specified time period.
Statistical Analysis
The primary hypothesis concerned effects of aprepitant on midazolam and was assessed by comparing the day 15 fold-change from baseline in AUC0- (day 15 AUC0-/baseline AUC0-) between the two treatment groups (midazolam with aprepitant, midazolam with placebo). Individual subjects' fold-change values were natural log transformed and evaluated with an ANOVA appropriate for a repeated-measures design. A 90% confidence interval (CI) for the between-treatment difference in arithmetic mean log fold-change (midazolam with aprepitant minus midazolam with placebo) was calculated using the mean square error from the ANOVA, referencing a t-distribution. The confidence limits were exponentiated to obtain a 90% CI for the ratio of true mean fold-change from baseline AUC0- (midazolam with aprepitant/midazolam with placebo). Given a repeated-measures design with 12 subjects completing the study in each treatment group and a true within-subject variance of 0.0525, there was a 0.96 probability that the 90% CI for the true aprepitant/placebo ratio of mean fold-change in midazolam AUC0- on day 15 would fall within the target interval of [0.70, 1.43], a conservative clinical definition of weak inhibition or induction.
As a secondary analysis, midazolam Cmax and clearance were evaluated in a similar fashion to AUC0-. For both tmax and half-life, the median difference (baseline subtracted from days 4, 8, and 15) and the estimated median shift based on the one-sample Hodges-Lehmann estimator of shift8 were calculated for each treatment. An estimate of the difference (shift) in the change from the day of interest versus baseline between subjects receiving a probe drug with aprepitant (group 1) and subjects receiving a probe drug with placebo (group 2) was calculated using the two-sample Hodges-Lehmann estimator.9 The between-treatment group differences in change from baseline for each day (4, 8, and 15) were analyzed using the Wilcoxon rank sum test. Tolbutamide data were analyzed in a similar fashion; additional exploratory analyses were performed based on CYP2C9 genotype.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Midazolam
Figure 1 shows the arithmetic mean plasma concentration profiles of midazolam following a single 2-mg i.v. dose given at baseline and on days 4, 8, and 15 following aprepitant or placebo, and Table I summarizes the effects of aprepitant or placebo on pharmacokinetic parameters for midazolam. The aprepitant 3-day regimen increased average plasma midazolam concentrations slightly on day 4, decreased midazolam concentrations slightly on day 8, and had virtually no effect on midazolam concentrations by day 15. The ratio (aprepitant/placebo) of geometric means for midazolam AUC0- fold-change from baseline was 1.25 on day 4 (90% CI = 1.09, 1.42; p = 0.007), consistent with a net slight inhibitory effect of aprepitant on i.v. midazolam metabolism, and 0.81 on day 8 (90% CI = 0.71, 0.92; p = 0.008), consistent with a slight inductive effect of aprepitant. By day 15, the ratio of the geometric means was close to unity at 0.96, with a 90% CI of (0.85, 1.10), which lies completely within the predefined target interval of [0.70, 1.43], consistent with a lack of effect of aprepitant on i.v. midazolam metabolism at this point in time. The midazolam Cmax geometric mean fold-changes from baseline on days 4, 8, and 15 following aprepitant were not significantly different from those following placebo, although effects on midazolam Cmax would be unlikely following bolus i.v. infusion of midazolam (Table I). Midazolam clearance after aprepitant was consistent with the plasma concentration findings (Table I). The ratios of geometric mean fold-changes in i.v. midazolam clearance were 0.80 on day 4 (90% CI = 0.70, 0.92; p = 0.007), consistent with a net inhibitory effect of aprepitant on midazolam metabolism; 1.24 on day 8 (90% CI = 1.09, 1.41; p = 0.008), consistent with a slight inductive effect; and 1.04 by day 15 (90% CI = 0.91, 1.18), consistent with a lack of effect of aprepitant on i.v. midazolam metabolism. There were no statistically significant differences in the changes from baseline of i.v. midazolam half-life between the aprepitant and placebo groups, which is consistent with the overall modest effects of aprepitant on i.v. midazolam pharmacokinetics (Table I).
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Tolbutamide
Figure 2 shows the mean plasma concentration profiles of oral tolbutamide at baseline and on days 4, 8, and 15 for the aprepitant and placebo groups, and Table II summarizes the effects of aprepitant or placebo on the pharmacokinetic parameters of tolbutamide. Following aprepitant, arithmetic average tolbutamide concentrations were decreased on days 4 and 8 and were returning to baseline on day 15. The ratio (aprepitant/placebo) of geometric means for tolbutamide AUC0- fold-change from baseline were 0.77 on day 4 (90% CI = 0.67, 0.88; p = 0.002) and 0.72 on day 8 (90% CI = 0.63, 0.82; p < 0.001), consistent with a slight induction effect of aprepitant on tolbutamide metabolism. By day 15, the ratio of the geometric means was 0.85 (90% CI = 0.74, 0.97; p = 0.05), which is closer to unity but still reflective of a slight induction effect of aprepitant. As shown in Table II, the ratios of geometric mean Cmax fold-change from baseline were 1.03 on day 4 (90% CI = 0.91, 1.16), 0.93 on day 8 (90% CI = 0.83, 1.05), and 0.96 on day 15 (90% CI = 0.85, 1.08). Slight decreases in median half-life were noted on days 4 and 8 in the aprepitant group. No statistically significant between-treatment differences in tmax were noted (Table II). The ratios (aprepitant/placebo) of geometric mean fold-changes from baseline in the urinary excretion of carboxytolbutamide and hydroxytolbutamide metabolites were 1.07 on day 4, 1.04 on day 8, and 1.00 on day 15 (Table III). Hence, the urinary excretion of these two metabolites appears to increase on days 4 and 8 and return to baseline on day 15, consistent with modest induction of tolbutamide metabolism but recovery by day 15.
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Seventeen of the 24 subjects were homozygous for the wild or "normal" allele (genotype 1/1; absence of either *2 or *3 alleles). These subjects would be expected to have "normal" CYP2C9 activity and would be classified as extensive metabolizers. Two subjects were found to have a single copy of the CYP2C9*2 allele (genotype 1/2), and 4 subjects had a single copy of the CYP2C9*3 allele (genotype 1/3). Since the *2 and *3 alleles both show decreased CYP2C9 activity significantly lower than that of the *1 allele, these subjects could be either extensive metabolizers or poor metabolizers and have a normal or decreased rate of metabolism of 2C9 substrates, respectively. One subject was homozygous for the CYP2C9*2 allele and would also be expected to be a poor metabolizer, with a decreased CYP2C9 activity compared with the 1/1 subjects. In a secondary analysis that looked at extensive CYP2C9 metabolizers only (genotype 1/1) and excluded all subjects with at least one allele of CYP*2 or CYP*3, findings similar to those described above for the overall analysis were noted.
Tolerability
No subjects discontinued the study, and no serious clinical, laboratory, or other adverse events were reported. Of the 119 nonserious adverse events reported, 56 were among the 12 subjects in the aprepitant group, and 63 were among the 12 subjects in the placebo group. Four patients (2 from each treatment group) reported adverse events that were considered drug related by the investigator (3 reports of mild somnolence and 1 report of mild nausea), and all adverse events resolved by the end of the study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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This study also examined the effects of the aprepitant CINV regimen on CYP2C9 using oral tolbutamide 500 mg as a CYP2C9 probe in healthy subjects who were CYP2C9*1 homozygotes, CYP2C9*1*2 heterozygotes, and CYP2C9*1*3 heterozygotes. The aprepitant regimen produced modest induction of CYP2C9 activity on days 4 and 8, as shown by average decreases versus placebo (23% on day 4 and 28% on day 8) in tolbutamide plasma AUC0-. The average decreases in the tolbutamide concentrations were accompanied by average increases in the urinary excretion of tolbutamide metabolites, and slight average decreases in tolbutamide half-life without change in Cmax were observed on days 4 and 8. On day 15, the tolbutamide AUC0- was still slightly (15%) lower on average compared with placebo, but the urinary excretion of tolbutamide metabolites had returned to baseline. Therefore, the slight effect on tolbutamide plasma AUC0- on day 15, which was within the hypothesized target interval of [0.70, 1.43], is likely not clinically relevant since the effects on plasma tolbutamide and urinary tolbutamide metabolites were approaching or had returned to baseline. These results are consistent with those observed previously in a study that examined the effect of the aprepitant regimen for CINV on warfarin, in which the aprepitant regimen produced modest induction of CYP2C9 activity, manifested as a decrease in the plasma concentration of S(-)-warfarin that appeared to be maximal by day 8.7 By comparison, induction of CYP2C9 activity by rifampin results in 
55% and 58% reductions of tolbutamide or warfarin AUC, respectively.13,14
These results indicate that the aprepitant regimen produces a transient, modest induction of CYP2C9 activity, such that coadministration of aprepitant with drugs known to be metabolized by CYP2C9 may result in lower plasma concentrations of these drugs. The degree of induction is not likely to be of clinical importance for most drugs that are CYP2C9 substrates (e.g., nonsteroidal anti-inflammatory drugs such as diclofenac). However, for CYP2C9 substrates with a narrow therapeutic index (e.g., S(-)-warfarin, phenytoin), this small effect could be clinically important.15
The distribution of CYP2C9 alleles in this study was consistent with reported frequencies of these alleles in the Caucasian population.15 One non-Caucasian subject carried a nonwild-type allele, which is consistent with the fact that the frequency of the CYP2C9*2 and CYP2C9*3 alleles is much lower in non-Caucasian populations.16 The modest CYP2C9 inductive effect of the aprepitant regimen was similar in the entire group (extensive and poor metabolizers), as well as among extensive metabolizers only. There were too few poor metabolizers to conduct a meaningful statistical analysis.
In summary, the 3-day dosing regimen of aprepitant recommended for the treatment of CINV has modest inductive effects on CYP3A4 and CYP2C9 that appear to be maximal around day 8 (i.e., 5 days after completion of the regimen) and are resolved (CYP3A4) or nearly resolved (CYP2C9) by day 15. For many drugs, these effects are unlikely to be clinically significant. However, for drugs with a narrow therapeutic index such as warfarin, a 30% reduction in plasma concentration might be clinically important. Therefore, in patients on chronic warfarin therapy, the prothrombin time (international normalized ratio [INR]) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle. Aprepitant may be administered to patients who receive chemotherapy agents metabolized by CYP3A4 (e.g., taxanes, vinca alkaloids, epipodophyllotoxins, ifosfamide, irinotecan) or by other CYPs. Since no chemotherapeutic agents are currently known to be metabolized predominantly by CYP2C9 and the induction of CYP3A4 activity is weak, it is unlikely that these inductive effects of aprepitant would significantly affect the pharmacokinetics of chemotherapeutic agents administered within the 12 days following completion of the aprepitant regimen for prevention of CINV.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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This study was funded by Merck Research Laboratories. Drs. Blum, Bradstreet, and Petty are members of the American Society for Clinical Pharmacology and Therapeutics.
Submitted for publication August 13, 2003; Revised version accepted November 26, 2003.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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4. Poli-Bigelli S, Rodriguez-Pereira, Guoguang-Ma J, Carides AD, Eldridge K, Evans JK, et al: The oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a randomized, double-blind, placebo controlled trial. Cancer 2003;97(12): 3090-3098.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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