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DRUG INTERACTIONS |
From Merck & Co, Inc, Whitehouse Station, New Jersey (Dr Krishna, Dr Bergman, Mr Larson, Ms Cote, Dr Wang, Mr Zeng, Mr Chen, Dr Wagner, Dr Herman) and SFBCI, Miami, Florida (Dr Lasseter, Ms Dilzer).
Address for reprints: Address for correspondence: Rajesh Krishna, PhD, FCP, Department of Clinical Pharmacology, Merck Research Laboratories, Merck & Co, Inc, 126 East Lincoln Avenue, Rahway, NJ 07065; e-mail: rajesh_krishna{at}merck.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t
, or C24 h, suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.
Key Words: Sitagliptin • DPP-4 inhibitor • P-glycoprotein • drug interaction • cyclosporine A
Sitagliptin ((2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine) is an orally active, potent, and selective DPP-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus.7 In particular, sitagliptin is highly selective and demonstrates at least a 2600-fold margin over activity against the closely related enzymes DPP8 and DPP9.8 Pharmacologic proof of concept has been established for sitagliptin in normoglycemic humans following both single- and multiple-dose administration.9,10 Specifically, sitagliptin inhibited plasma DPP-4 activity dose dependently while increasing the postprandial rise in active GLP-1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen and was found to be well tolerated.9,10
Sitagliptin has been shown to be a substrate for P-glycoprotein (Pgp) by in vitro investigations. In polarized LLC-PK1 cell lines expressing human and mouse Pgp, sitagliptin exhibited vectorial transport, suggesting that it was a substrate for Pgp. Studies in MDR1-transfected cell lines indicated that at clinically relevant concentrations, sitagliptin did not inhibit the bidirectional transport of radiolabeled digoxin.11
Currently, there is no specific guidance on a clinically useful probe Pgp inhibitor to assess the impact of Pgp inhibition on the systemic exposures of the Pgp substrate. A European Federation of Pharmaceutical Sciences (EUFEPS) conference on optimizing drug development discussed this specific issue more broadly for the first time and was a subject of a published work in 2001.12 Subsequently, a consensus view on this subject by participating PhRMA member companies for the conduct of in vitro and in vivo drug-drug interaction studies involving phase I (CYP) and phase II (UGT, ST) metabolic and transporter interactions was published in 2003.13 Most recently, at the time this manuscript went into revision, draft US Food and Drug Administration (FDA) guidance on this subject was issued in September 2006.14 This draft guidance suggests the use of cyclosporine (CSA), ritonavir, and verapamil as Pgp inhibitors. All 3 of these probe inhibitors present safety hazards when given to healthy subjects long term at exposures required to discern Pgp inhibition, thus limiting their use to single-dose administration. These considerations are further compounded by the fact that at the present time, there is no marketed drug that could be used as a specific and selective probe inhibitor of Pgp. Among Pgp inhibitors, the most potent ones include CSA, quinidine, ketoconazole, clarithromycin, and atorvastatin.15-19 Among these, CSA appears to be the most potent at plasma concentrations that are therapeutically possible. Quinidine, ketoconazole, clarithromycin, and atorvastatin all produce human plasma concentrations at therapeutic doses that are more than an order of magnitude lower than the IC50 or Ki required for Pgp inhibition.15 The clinically relevant plasma concentrations of CSA as a Pgp inhibitor range from approximately 1000 to 5000 ng/mL.20 A single oral dose of 300 mg CSA yields mean peak plasma concentrations of approximately 1000 ng/mL, with an elimination half-life of approximately 8 hours. It was therefore expected that a dose of 600 mg CSA would provide exposures that are more than adequate to test the concept of intestinal Pgp inhibition.
Cyclosporine is known to inhibit other enzymes (eg, CYP3A4) and transporters (eg, OATP2) and, as such, is not a specific Pgp inhibitor.21 However, given the fact that metabolism plays a minor role in the elimination of sitagliptin,22 it was reasoned that any substantial effects on sitagliptin pharmacokinetics could be largely, although not necessarily exclusively, attributed to affects on Pgp.
A single oral dose of 100 mg, the clinical dose of sitagliptin in patients with type 2 diabetes, was chosen for this study. Given that sitagliptin is minimally cleared via metabolism and is predominantly renally eliminated (>70% of total clearance) with a high oral bioavailability (approximately 87%),22 it was considered unlikely that CSA would have a clinically meaningful pharmacokinetic interaction with sitagliptin. Based on the clinical profile of sitagliptin, a confidence interval limit of 0.5 to 2.0 was selected for area under the plasma concentration time curve (AUC) as indicating changes that would not be considered clinically relevant because there has been no evidence that a 2-fold change in sitagliptin exposure has a meaningful effect on the safety and/or pharmacodynamic activity of sitagliptin. Thus, based on clinical experience thus far, the therapeutic index of sitagliptin appears to be wide. AUC was chosen as the clinically relevant pharmacokinetic parameter because overall exposure most closely correlates with efficacy and tolerability.23,24
In this study, CSA was used as a putative probe Pgp inhibitor to evaluate the potential effect of Pgp inhibition on single-dose sitagliptin pharmacokinetics. The effect of sitagliptin on cyclosporine pharmacokinetics was not examined in this study as in vitro data indicated that sitagliptin was not an inhibitor of Pgp, and no interaction was expected. Furthermore, assessment of the effect of sitagliptin on the pharmacokinetics of digoxin, a Pgp substrate, has already been investigated in another study.25 This article discusses the potential use of CSA as a probe Pgp inhibitor under single-dose administration for a Pgp substrate for which CYP3A is a very minor component in its disposition.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Study Design
This was an open-label, 2-period crossover study. Subjects were randomized to the sequence of 2 treatments. In 1 treatment, subjects received a single oral dose of 600 mg CSA (NEORAL) with a single oral dose of 100 mg sitagliptin. In the other treatment, subjects received a single oral dose of 100 mg sitagliptin alone. There was at least a 2-week washout period between periods. Subjects were administered the treatments after an overnight fast of at least 8 hours. Drug was administered between 8:00 AM and 10:00 AM. All doses of study medication were witnessed, and each dose of study medication was administered at approximately the same time each day with approximately 240 mL of water (sitagliptin only) or 480 mL of water (sitagliptin and CSA). A higher volume of water was given because of the size and number of CSA capsules.
Blood (5 mL) was drawn via an indwelling intravenous catheter in a forearm vein and processed by centrifugation for determination of plasma sitagliptin concentration at predose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 24, 32, 48, and 72 hours post-dose. Urine collections occurred predose and at the following intervals: 0 to 6, 6 to 12, 12 to 24, and 24 to 48 hours postdose. Urine was kept on ice during collection, with the volume recorded to the nearest 5 mL, and a 4-mL aliquot was saved for analysis. Plasma and urine samples were stored at -70°C until assayed.
Safety
Physical examinations, vital signs, 12-lead electrocardiograms (including assessment for QTc and PR interval prolongation), and safety laboratory measurements comprising routine hematology, serum chemistry (including liver transaminases), and urinalysis were performed prestudy, at various time points postdosing, and at poststudy. Adverse experiences were monitored throughout the study. The investigator evaluated all clinical adverse experiences in terms of intensity (mild, moderate, or severe), duration, severity, outcome, and relationship to study drugs. To minimize the risk associated with high-dose CSA, women of childbearing potential were not enrolled in this study.
Bioanalytical Methods
Plasma and urine samples were analyzed for sitagliptin concentrations using an assay method that has been published.26 Briefly, samples were directly injected onto a Cohesive Technologies high-turbulent liquid chromatography system (HTLC). Analyte and internal standard were detected by tandem mass spectrometry (MS/MS) using selected reaction monitoring (SRM) with turbo-ionspray interface in the positive ion mode. The lower limit of quantitation (LLOQ) for the plasma assay was 0.5 ng/mL, and the linear calibration range was 0.5 to 1000 ng/mL. The LLOQ for the urine assay was 0.1 µg/mL, and the linear calibration range was 0.1 to 50 µg/mL. The selectivity of the plasma and urine assay was evaluated by testing each of the blank control plasma or urine samples from 6 different sources. No endogenous interferences were found at the retention times of sitagliptin and the internal standard. Intraday accuracy and precision of the method were evaluated by analyzing 5 sets of calibration standard curves prepared in 5 different lots of human control plasma or urine. For the plasma assay, the precision (relative standard deviation [RSD%], n = 5) ranged from 2.4% to 9.0% and the accuracy from 98.0% to 103% of the nominal value. For the urine assay, the precision (RSD%, n = 5) ranged from 2.3% to 6.5% and the accuracy from 96.9% to 106% of the nominal value.
The intraday precision (RSD%, n = 5) for plasma quality control (QC) samples varied from 2.0% to 5.3% and accuracy from 103% to 105% of the nominal value. The intraday precision (RSD%, n = 5) for urine QC samples varied from 1.8% to 2.6% and accuracy from 96.2% to 106% of the nominal value. The interday variability of the method was evaluated using the daily QC results. For the plasma assay, the interday precision and accuracy represents 100 sets of low, middle, and high QC samples over an 8-month period. The precision (RSD%, n = 100) varied from 6.3% to 9.0% and the accuracy from 98.8% to 104% of the nominal value. For the urine assay, the interday precision and accuracy represents 52 sets of low, medium, and high QC samples over a 6-month period. The precision (RSD%, n = 52) varied from 3.8% to 5.5% and accuracy from 102% to 105% of the nominal value. These performance characteristics indicate that the assay method employed for sitagliptin was robust, precise, and sensitive.
Pharmacokinetic Methods
Apparent terminal rate constant (
) was estimated by regression of the terminal log-linear portion (determined by inspection) of the plasma concentration-time profile; t was calculated as the quotient of ln(2) and . Area under the plasma concentration-time curve to the last time point was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. The AUC0- value was estimated as the sum of AUC to the last measured concentration, with the extrapolated area given by the quotient of the last measured concentration and . The Cmax, tmax, and C24 h values were obtained by inspection of the plasma concentration data.
The amount of sitagliptin excreted unchanged in urine in each collection interval was determined by the product of the urine concentration and the urine volume. The fraction of the sitagliptin dose that was excreted unchanged in urine over the dosing intervals (fe,0-48 h) was determined by the quotient of the sum of sitagliptin collected over all dosing intervals and the dose administered. The fraction of the sitagliptin dose that was excreted unchanged in urine (fe,0-) was determined as the product of fe,0-48 h and the AUC0-/AUC0-48 h ratio. Renal clearance (ClR) was determined as the quotient of fe,0-48 h • Dose and AUC0-48 h.
Creatinine Clearance
Creatinine clearance was determined using a 24-hour urine collection method. The total urine produced during each 24-hour interval was collected in urine container(s) provided by the study unit. The 24-hour start and stop times of the collections were recorded. All urine samples were refrigerated at 4°C until returned to the study unit. The total volume of urine was measured and recorded. One subject was excluded from the statistical analysis of creatinine clearance because of a suspected erroneous value of 657 mL/min at 24 hours postdose in period 1. A subsequent repeat was not possible until the second 24-hour interval, and the repeat value was 115 mL/min.
Statistical Methods
The effect of a 600-mg single-dose administration of CSA on the 100-mg single dose of sitagliptin plasma pharmacokinetic parameters (AUC0-, Cmax, tmax, and apparent t) was evaluated using an analysis of variance (ANOVA) model appropriate for a 2-period, balanced crossover design with terms sequence, subject within sequence, period, and treatment (sitagliptin with and without CSA). The same ANOVA model was used to assess the between-treatment differences with respect to the urinary pharmacokinetic parameters of CLR and fe,0-. Appropriate transformations on the sitagliptin pharmacokinetic parameters and creatinine clearance were used (ie, log transformation for AUC0-, Cmax, CLR, creatinine clearance, and C24 h; rank transformation for tmax; inverse for apparent t and unadjusted fe,0-). Back-transformed summary statistics and inferential results were to be reported for pharmacokinetic parameters of sitagliptin in the presence and absence of CSA. The normality assumption of the model was examined graphically and tested by using the Shapiro-Wilk's statistic and was generally satisfied.
A 90% confidence interval (CI), based on the t distribution, was generated from the above ANOVA model for the AUC0- geometric mean ratio, GMR (sitagliptin + CSA/sitagliptin). This 90% CI was then compared to the prespecified comparability bounds of [0.50, 2.00]. The hypothesis that the coadministration of a 600-mg single dose of CSA does not alter the 100-mg single-dose pharmacokinetics of sitagliptin in healthy male subjects in a clinically meaningful manner was to be satisfied if the 90% CI for the AUC(0-) GMR (sitagliptin + CSA/sitagliptin) was contained within the interval (0.50, 2.00). Back-transformed summary statistics, including a between-treatment GMR (sitagliptin + CSA/sitagliptin) for CLR and the corresponding 90% CI, was presented.
Back-transformed summary statistics, including a between-treatment GMR (sitagliptin + CSA/sitagliptin) for creatinine clearance and the corresponding 90% CI, was determined. For 1 subject, a reliable estimate of creatinine clearance for the 24 hours following the sitagliptin + cyclosporine treatment could not be determined; therefore, the primary analysis was performed excluding this subject. However, using a creatinine clearance value that was obtained between 24 and 48 hours postdose, consistent between-treatment comparisons were observed.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Plasma Pharmacokinetics
Mean sitagliptin plasma concentration profiles are presented in Figure 1. Mean plasma concentrations for the sitagliptin + CSA treatment were somewhat higher over the first 12 hours postdose as compared to those following sitagliptin treatment alone but were generally similar beyond 12 hours postdose. The single-dose sitagliptin AUC0- GMR (sitagliptin + CSA/sitagliptin) was 1.29, with a corresponding 90% CI of (1.24, 1.34), which fell within the prespecified comparability bounds of (0.50, 2.00) (Table I). Although no statistically significant difference was observed in sitagliptin C24 h between treatments (P > .200), the geometric mean Cmax was approximately 68% (90% CI [1.36, 2.08]) higher for sitagliptin + CSA versus sitagliptin administered alone (Table I). The median sitagliptin tmax values were 2.25 and 4.00 hours for the sitagliptin + CSA and sitagliptin groups, respectively, and no statistically significant between-treatment difference was observed (P > .200).
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The sitagliptin harmonic mean apparent t values were 10.6 and 11.6 hours for the sitagliptin + CSA and sitagliptin groups, respectively. Although the mean t values are numerically similar, a statistically significant between-treatment difference was observed (P = .011). The observed differences are not considered likely to be clinically relevant.
Renal Excretion
Mean ClR values during each urine collection intervals are presented in Figure 2. There are no apparent differences in ClR for any of the collection intervals. The sitagliptin ClR GMR (sitagliptin + CSA/sitagliptin) was 1.01, with a 90% CI of (0.87, 1.18) (Table I). No statistically significant differences were observed between treatments (P > .200).
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The mean sitagliptin fe,0- values were 0.838 and 0.658 for the sitagliptin + CSA and sitagliptin groups, respectively, and a statistically significant between-treatment difference was observed (P = .016). These results (Table I) are consistent with the observed higher AUC and Cmax sitagliptin values in the presence of CSA. Thus, because renal clearance of sitagliptin is not altered by CSA, the observed differences in sitagliptin fe,0- are likely due to changes in sitagliptin bioavailability in the presence of CSA.
The least squares mean creatinine clearance values (Table I) were 121 and 92 mL/min for the sitagliptin + CSA and sitagliptin groups, respectively, and no statistically significant between-treatment difference was observed (P > .242).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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In this study, coadministration of a single oral CSA dose with a single dose of sitagliptin increased maximal plasma concentrations of sitagliptin without a meaningful effect on overall exposure. The key pharmacokinetic parameter for sitagliptin is AUC0-, which increased by approximately 28% in the presence of CSA; however, the 90% CI for the GMR was contained within the prespecified bounds of 0.5 to 2.0, indicating that the magnitude of the observed interaction may not be clinically meaningful. Based on clinical studies completed to date, sitagliptin appears to have a wide therapeutic index.9,10,23,24 Notably, single doses of up to 800 mg9 and multiple doses of up to 600 mg per day in healthy male subjects10 have been generally well tolerated. In the presence of CSA, sitagliptin Cmax was increased by approximately 68%. Due to the apparent wide therapeutic index of sitagliptin, a 68% increase in Cmax at a therapeutic dose level (eg, 100 or 200 mg) is unlikely to be clinically meaningful. Interestingly, the effect of CSA on sitagliptin Cmax was associated with greater variability than the effect on AUC. This could be due to the variability in Pgp expression along the gastrointestinal tract27 and/or in part to the number of CSA capsules (6 x 100 mg) administered.
Sitagliptin C24 h was generally similar in the presence and absence of CSA. Although a statistically significant effect on terminal half-life in the presence and absence of CSA was observed, the observed changes are not considered to be clinically meaningful. Sitagliptin renal clearance was also not altered by CSA.
Taken together with data from preclinical and in vitro studies, results from this study are consistent with the fact that sitagliptin may be a Pgp substrate. Given the finding that renal clearance of sitagliptin (the major route of elimination accounting for approximately 70% of total plasma clearance22) was relatively unchanged in the presence and absence of CSA, it is plausible that the observed increase in sitagliptin Cmax in the presence of CSA is mediated by increasing the rate and/or extent of absorption of sitagliptin via inhibition of intestinal Pgp. Because the renal clearance of sitagliptin was not affected by CSA, the results of this study did not support the role of Pgp in the renal elimination of sitagliptin in humans. However, it is also possible that the effects on renal clearance may not have been observed because plasma CSA concentrations achieved were probably not high enough to inhibit renal Pgp-mediated transport.
Effects of CSA on total sitagliptin exposure (ie, AUC) may not be completely explained by inhibition of Pgp at the level of the intestine given that sitagliptin exhibits high absolute oral bioavailability (
87%) in humans in the absence of CSA. Other potential mechanisms that might explain this increase in sitagliptin AUC may include an alteration in the nonrenal clearance of sitagliptin by CSA. This may include possible inhibition of CYP3A4-mediated metabolism of sitagliptin, which is only a minor pathway of clearance for sitagliptin.22
The interaction between sitagliptin and digoxin, a Pgp substrate that is also a narrow therapeutic index drug, has been investigated in a separate study.25 At the 100-mg sitagliptin clinical dose, the digoxin, a known Pgp substrate, AUC0- GMR (digoxin + sitagliptin/digoxin) 90% CI fell within bioequivalence bounds of (0.80, 1.25). The observed increases of 11% in plasma digoxin AUC after concomitant administration with sitagliptin are not explained by inhibition of digoxin renal clearance by sitagliptin as the ClR for digoxin was not reduced by sitagliptin. The slight increases in digoxin plasma concentrations may be due to enhanced digoxin absorption in the presence of sitagliptin and unrelated to Pgp-related effects because sitagliptin is not an inhibitor of Pgp-mediated transport at high concentrations based on in vitro assessments.11
The CSA dose used in this study was nearly 2- to 3-fold higher than a typical clinically applicable dose of CSA and was used primarily to test the impact of intestinal Pgp inhibition on sitagliptin pharmacokinetics.28 In clinical practice, organ transplant patients are typically maintained on a stable antirejection regimen that includes CSA.28 Generally, 75- to 200-mg bid doses of CSA are associated with therapeutically relevant whole-blood CSA concentrations of approximately 150 to 200 ng/mL. This compares to the concentrations of approximately 2000 to 3000 ng/mL that would be expected following a single oral dose of 600 mg. Given the fact that the CSA concentrations achieved were nearly 10-fold higher than would be expected in routine clinical use, the effects observed here would exceed the magnitude of potential effects encountered in clinical practice.
Currently, there is no marketed drug that could be used as a specific and selective probe inhibitor of Pgp. A draft US FDA guidance on this subject was issued in September 2006.14 This draft guidance suggests the use of CSA, ritonavir, and verapamil as Pgp inhibitors. All 3 of these probe inhibitors present safety hazards when given to healthy subjects long term at exposures required to discern Pgp inhibition, thus limiting their use to single-dose administration.20 Although some selective Pgp inhibitors are being developed as potential modulators of multidrug resistance in cancer, there is no marketed drug that could be used as a specific and selective probe inhibitor of Pgp. Among Pgp inhibitors, the most potent ones include CSA, quinidine, ketoconazole, clarithromycin, and atorvastatin. Quinidine, ketoconazole, clarithromycin, and atorvastatin all produce human plasma concentrations at therapeutic doses that are more than an order of magnitude lower than the IC50 or Ki required for Pgp inhibition (Table II).15 The clinically relevant plasma concentrations of CSA as a Pgp inhibitor range from approximately 1000 to 5000 ng/mL.20,29 A single oral dose of 300 mg CSA yields mean peak plasma concentrations of approximately 1000 ng/mL, with an elimination half-life of approximately 8 hours. It was therefore expected that a dose of 600 mg CSA would provide exposures that are more than adequate to test the concept of intestinal Pgp inhibition and presents the best available probe inhibitor of Pgp. Moreover, these results on sitagliptin pharmacokinetics obtained using CSA can be reasonably extrapolated to other Pgp inhibitors that would be expected to produce changes of an even lower magnitude.
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In this study, we limited the use of CSA to a single dose, given the safety risks imposed by the administration of CSA to healthy volunteers. A vast literature exists where CSA has been shown, at doses of approximately 4 to 5 mg/kg, to be associated with acute renal and immunological effects in healthy subjects.30-32 These studies have suggested dosedependent reductions in the glomerular filtration rate (GFR) by CSA, mediated presumably via vasoconstrictive effects. These findings suggest that the reduction in GFR was observed at the range of plasma concentrations of CSA, which are presumably in the range of clinically significant Pgp effects.
There are a few recent examples where CSA was used as a probe inhibitor in a drug interaction study.33 Most of these studies have been performed in the transplant population.34-36 Because endothelins may play a role in CSA-induced renal vasoconstriction, the effect of multiple oral CSA (Sandimmun Neoral) doses on bosentan (Ro47-0203), a mixed ET-A and B receptor antagonist, was assessed in healthy volunteers.37,38 The study was presumably not designed a priori to study Pgp inhibition of bosentan. In a double-blind, randomized, placebo-controlled, crossover study in 8 healthy male subjects, subjects received 500 mg bid bosentan + 300 mg bid CSA or 300 mg bid CSA + placebo for a period of 8 days. Target trough plasma concentrations of 200 to 250 ng/mL at steady state were attained by adjusting CSA doses. CSA increased bosentan Cmax and AUC by 2-fold on day 8, but there was no effect on half-life. It appears that bosentan is metabolized by 3A4 and is a substrate of Pgp.37 In the same study, bosentan had no effect on GFR, whereas CSA + placebo caused GFR to fall from 120 ± 90 mL/min to 103 ± 18 mL/min. This decrease in GFR mediated by CSA is unlikely to have caused an effect on bosentan exposure as bosentan is minimally eliminated in urine (3% recovered in urine of humans).
As CSA has been shown to cause a statistically significant reduction in GFR after multiple oral dose administration in healthy subjects, this effect may potentially alter the pharmacokinetics of sitagliptin at the level of the kidney independent of the inhibition of transport properties. For these reasons, a single dose of CSA was used in this probe study under stringently monitored circumstances. Based on measurements of creatinine clearance as a marker of GFR, no such differences were observed between the 2 treatments with respect to creatinine clearance in this study. The administration of sitagliptin in the presence and absence of a single oral dose of CSA was found to be generally well tolerated in the study population.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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GMR (sitagliptin + CSA/sitagliptin) was 1.29, with a 90% CI of (1.24, 1.34), within the prespecified bounds of (0.50, 2.00); sitagliptin Cmax GMR and 90% CI was 1.68 (1.36, 2.08). The observed increase in maximal plasma concentrations of sitagliptin is not expected to be clinically meaningful at the therapeutically relevant sitagliptin doses. Single oral doses of CSA do not meaningfully affect sitagliptin tmax, C24 h, or apparent terminal half-life. Single oral doses of CSA do not meaningfully alter the renal clearance of sitagliptin—that is, the sitagliptin ClR GMR (sitagliptin + CSA/sitagliptin) was 1.01, with a 90% CI of (0.87, 1.18). Taken together with preclinical data with sitagliptin, the observed effects with CSA, a probe Pgp inhibitor, suggest that sitagliptin is a Pgp substrate. Single doses of sitagliptin with or without single doses of CSA are generally well tolerated. Furthermore, our results rationalize the use of a single high-dose CSA as a probe inhibitor of Pgp for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism. |
ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Dr Wang's current affiliation is GlaxoSmithKline, King of Prussia, Pennsylvania.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27: 1047-1053.
2. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes scientific review. JAMA. 2002;287: 360-372.
3. Ahren B. Type 2 diabetes, insulin secretion and beta cell mass. Curr Mol Med. 2005;5: 275-286.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12: 87-100.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Villhauer EB, Coppola GM, Hughes TW. DPP-IV inhibition and therapeutic potential. Ann Rep Med Chem. 2001;36: 191-200.
6. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab. 2004;89: 2078-2084.
7. Kim D, Wang L, Beconi M, et al. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005;48: 141-151.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Lankas GR, Leiting L, Roy R, et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005;54: 2988-2994.
9. Herman G, Stevens C, Van Dyck K, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005;78: 675-688.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Bergman A, Stevens C, Zhou C, et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006;28: 55-72.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Vincent SH. Discovery and early development of sitagliptin (MK-0431) [abstract]. In: Drug Metabolism Graduate Student Symposium, Rahway, NJ, 2005.
12. Tucker G, Houston JB, Huang S-M. Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential—toward a consensus. Clin Pharmacol Ther. 2001;70: 103-114.[CrossRef][Medline] [Order article via Infotrieve]
13. Bjornsson TD, Callaghan JT, Einolf HJ. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J Clin Pharmacol. 2003;43: 443-469.
14. Food and Drug Administration (FDA). Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, and Implications for Dosing and Labeling. Rockville, Md: FDA; 2006.
15. Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y. Impact of drug transporter studies in drug discovery and development. Pharmacol Rev. 2003;55: 425-461.
16. Zhou S, Yuan Chan S, Cher Goh B, et al. Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet. 2005;44: 279-304.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
17. Wakasugi H, Yano I, Ito T, et al. Effect of clarithromycin on renal excretion of digoxin: interaction with P-glycoprotein. Clin Pharmacol Ther. 1998;64: 123-128.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Wang E, Casciano CN, Clement RP, Johnson WW. HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm Res. 2001;18: 800-806.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Damkier P, Hansen LL, Brosen K. Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. Br J Clin Pharmacol. 1999;48: 829-838.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Krishna R, Mayer L. Multidrug resistance in cancer: mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci. 2000;11: 265-283.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. Kusuhara H, Sugiyama Y. Drug-drug interactions involving the membrane transport process. In: Rodrigues AD, ed. Drug-Drug Interactions. New York: Marcel Dekker; 2001: 123-188.
22. Vincent SH, Reed JR, Bergman AJ, et al. Metabolism and excretion of the DPP-4 inhibitor [14C]sitagliptin (MK-0431) in humans. Drug Metab Dispos. In press.
23. Stein PP, Williams-Herman DE, Khatami H, Meininger GE, Kaufman KD, Amatruda J. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, was well tolerated in patients with type 2 diabetes: pooled results from 4 pivotal phase III studies [abstract]. In: American Diabetes Association 66th Annual Scientific Session, Washington, DC, 2006.
24. Hanefeld M, Herman GA, Mickel C, et al. Effect of MK-0431 (sitagliptin), a dipeptidyl peptidase IV (DPP-IV) inhibitor, on glycemic control after 12 weeks in patients with type 2 diabetes [abstract]. In: European Association for the Study of Diabetes 41st Annual Meeting (EASD), Athens, Greece, 2005.
25. Miller JL, Migoya EM, Talaty JE, et al. The effect of MK-0431 on the pharmacokinetics of digoxin after concomitant administration for 10 days in healthy subjects: results of a multiple-dose, double-blind, randomized, placebo-controlled study [abstract]. In: American Society for Clinical Pharmacology and Therapeutics 107th Annual Meeting (ASCPT), Baltimore, Md, 2006.
26. Zeng W, Musson DG, Fisher AL, Wang AQ. Determination of MK-0431 in human plasma using high turbulence liquid chromatography online extraction and tandem mass spectrometry. Rapid Commun Mass Spectrom. 2006;20: 1169-1175.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
27. Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther. 2006; 109: 137-161.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
28. Cyclosporine. In: Burton M, Shaw L, Schentag J, eds. Applied Pharmacokinetics and Pharmacodynamics: Principles of Therapeutic Drug Monitoring. Vancouver, Wash: Lippincott Williams & Wilkins; 2005: 512-528.
29. Rodrigues AD. Drug-Drug Interactions. New York: Marcel Dekker; 2001.
30. De Nicola L, Libetta C, Memoli B, et al. Acute renal and immunological effects of low-dose cyclosporine in humans. Nephrol Dial Transplant. 1995;10: 1739-1744.
31. Hansen J, Johansen NJ, Mollerup HM, et al. Effects of nitric oxide blockade and CSA on cardiovascular and renal function in normal man. J Hyperten. 1999;17: 1707-1713.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
32. Hansen J, Fogh-Andersen N, Christensen NJ, Strandgaard S. Cyclosporine-induced hypertension and decline in renal function in healthy volunteers. J Hyperten. 1997;15: 319-326.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
33. Huang SM. Drug-drug interactions. In: Krishna R, ed. Applications of Pharmacokinetic Principles in Drug Development. New York: Springer Science; 2004.
34. Bergman AJ, Burke B, Larson P, et al. Interaction of single-dose ezetimibe and steady-state cyclosporine in renal transplant patients. J Clin Pharmacol. 2006;46: 328-336.
35. Simonson S, Raza A, Martin PD, et al. Rosuvastatin pharmacokinetics in heart transplant patients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther. 2004; 76: 167-177.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
36. Muck W, Mai I, Fritsche L, et al. Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporinetreated kidney transplant recipients. Clin Pharmacol Ther. 1999; 65: 251-261.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
37. FDA clinical pharmacology and biopharmaceutics review report: summary basis for approval of bosentan (Ro47-0203). Available at: http://www.fda.gov/cder/foi/nda/2001/21-290_Tracleer.htm. Accessed May 10, 2006.
38. Binet I, Wallnofer A, Weber C, et al. Renal hemodynamics and pharmacokinetics of bosentan with and without CSA. Kidney Int. 2000;57: 224-231.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
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