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A Study of the Pharmacokinetic Interaction of Istradefylline, a Novel Therapeutic for Parkinson's Disease, and Atorvastatin

From Kyowa Pharmaceutical Inc, Princeton, New Jersey (Dr Rao, Dr Sussman, Ms Wang, Dr Chaikin); Barry Dvorchik and Associates, Tampa, Florida (Dr Dvorchik); Kyowa Hakko Kogyo Co Ltd, Shizuoka, Japan (Mr Yamamoto); and Kyowa Hakko Kogyo Co Ltd, Tokyo, Japan (Dr Mori, Mr Uchimura).

Address for reprints: Niranjan Rao, PhD, Kyowa Pharmaceutical Inc, 212 Carnegie Center, Suite 101, Princeton, NJ 08540; e-mail: rao.niranjan{at}kyowa-kpi.com.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The effect of steady-state istradefylline, an agent for Parkinson's disease with P-glycoprotein and CYP3A inhibitory activity, on the pharmacokinetics of atorvastatin and its metabolites was evaluated in healthy volunteers. A single 40-mg dose of atorvastatin was administered to 20 subjects. After a 4-day washout, subjects received a single 40-mg atorvastatin dose following 40 mg istradefylline (n = 16) or placebo (n = 4) daily for 14 days. Plasma samples collected for 96 hours after atorvastatin administration, alone and in combination, were analyzed for atorvastatin, orthohydroxy atorvastatin, and parahydroxy atorvastatin. Istradefylline increased atorvastatin C_max (53%), AUC_0- (54%), and t (27%); and increased AUC_0- for orthohydroxy atorvastatin (18%), but had no significant effect on its C_max or t; and had minimal effect on parahydroxy atorvastatin AUC_0-. The lack of inhibition by istradefylline on metabolite systemic exposure, combined with increased atorvastatin systemic exposure, suggests a predominant P-glycoprotein inhibitory effect of istradefylline.

Key Words: Istradefylline • atorvastatin • pharmacokinetics • drug interaction

Istradefylline (KW-6002) is a selective adenosine A_2A–receptor antagonist in late-stage clinical development as adjunctive treatment for patients with Parkinson's disease. In a 6-week proof-of-principle study, Bara-Jimenez et al³ showed that istradefylline potentiated the anti-Parkinsonian action of low-dose levodopa with improvement in classic Parkinsonian symptoms (resting tremor by 72%, rigidity by 43%, bradykinesia by 38%). In 12-week, double-blind, multicenter studies of patients with advanced Parkinson's disease and motor fluctuations, istradefylline reduced the percentage and amount of awake time spent in the "off" state, periods of time when Parkinson's symptoms are not adequately controlled (ie, decreased the duration of the wearing-off phenomenon).^4,5

Drugs that lower cholesterol are frequently prescribed to the population in the same age range as patients with Parkinson's disease. In particular, atorvastatin is a commonly prescribed drug in this group, and current prescribing practices point to the use of increasingly higher daily doses. In vitro studies suggest the importance of atorvastatin metabolism by the cytochrome P450 3A (CYP3A) isoenzyme,^6,7 consistent with increased plasma concentrations of atorvastatin and decreased concentrations of CYP3A-mediated metabolites in humans after coadministration with erythromycin⁸ or itraconazole,⁹ both known CYP3A inhibitors. Two active metabolites, 2-hydroxy-atorvastatin (orthohydroxy atorvastatin) and 4-hydroxy-atorvastatin (parahydroxy atorvastatin), are formed by CYP3A metabolism of atorvastatin.^6,9-11 Atorvastatin is also a substrate for P-glycoprotein (P-gp).⁷ Treatment with istradefylline, a CYP3A and P-gp inhibitor, therefore, has the potential to interact with atorvastatin. The present study examines the effect of steady-state istradefylline on the single-dose pharmacokinetics of atorvastatin and its metabolites, ortho- and parahydroxy atorvastatin.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study Design
The protocol and informed consent form were reviewed and approved by the Independent Institutional Review Board Inc in Plantation, Fla, in accordance with good clinical practice guidelines, the Declaration of Helsinki, and Title 21 Code of Federal Regulations, Parts 50, 56, and 312. Twenty nonsmoking, healthy, male volunteers participated in this phase I, single-center, double-blind, placebo-controlled, randomized study. Subjects were enrolled if they met all inclusion criteria, including body mass index (BMI) of 18.5-34.9, and signed a written informed consent. Subjects were excluded if they had any condition possibly affecting drug absorption; a history of clinically significant gastrointestinal, cardiovascular, hepatic, psychiatric, or neurologic disease; consumed grapefruit juice or alcohol within 72 hours before baseline; used drugs of abuse, xanthine- or tobacco-containing products; or had been treated within 30 days before baseline with any investigational drug. All subjects received a single 40-mg dose of atorvastatin on day 1 with subsequent plasma sampling for pharmacokinetic analysis. After a 4-day washout period, the subjects (on day 5) were randomly assigned to receive either 40 mg/d istradefylline (n = 16) or placebo (n = 4) for 17 days (days 5-21). On day 18 (14 days of istradefylline dosing), each subject received a single oral 40-mg dose of atorvastatin with plasma sampling during a 96-hour period for pharmacokinetic analysis. Subjects were discharged on day 23 and returned approximately 1 week (±2 days) after discharge for a follow-up visit to evaluate safety.

Blood Sampling
Plasma samples for the determination of concentrations of atorvastatin and its metabolites (ortho- and parahydroxy atorvastatin) were collected from days 1 through 5 and from days 18 through 23, with samples collected predose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after the administration of atorvastatin on days 1 and 18. On days 6, 11, and 18, plasma samples were collected immediately before dosing with istradefylline to confirm istradefylline systemic exposure.

Analytical Method for Quantification of Atorvastatin
Analysis of plasma concentrations of atorvastatin and its orthohydroxy and parahydroxy metabolites was performed by SFBC Analytical Laboratories Inc. (North Wales, Pa) using a validated high-performance liquid chromatography (HPLC)/mass spectrometry detection method (LC/MS/MS) (SCIEX API4000 series; MDS SCIEX, Concord, Ontario, Canada) with a detection range of 0.25 to 100 ng/mL. Atorvastatin, orthohydroxy atorvastatin, and parahydroxy atorvastatin and the internal standards were extracted by liquid-liquid extraction from sodium heparin human plasma. The transition ion m/z 559.2 440.3 was monitored for atorvastatin and the transition ion m/z 575.3 440.3 was monitored for orthohydroxy atorvastatin and parahydroxy atorvastatin. A plasma blank, a plasma blank with internal standard, and 3 levels of quality control (QC) samples (in duplicate) were run with each curve. Blank human plasma samples were chromatographed, and no peaks were found at transition ions m/z 559.2 440.3 (atorvastatin), m/z 575.3 440.3 (orthohydroxy atorvastatin and parahydroxy atorvastatin), m/z 564.2 440.3 (atorvastatin-d₅), and m/z 580.2 445.3 (orthohydroxy atorvastatin-d₅ and parahydroxy atorvastatin-d₅). This demonstrated that there was no interference from endogenous matrix constituents. The precision of the assay (%CV) for atorvastatin QC samples ranged from 1.07% to 3.34%. The accuracy (%RE) at all concentrations for atorvastatin ranged from –2.43% through 1.69%. For orthohydroxy atorvastatin and parahydroxy atorvastatin, the %CV for QC samples ranged from 2.21% to 7.29% and from 1.95% to 7.29%, respectively. The %RE at all concentrations for orthohydroxy atorvastatin and parahydroxy atorvastatin ranged from 0.78% to 2.85% and from 1.40% to 3.79%, respectively. For atorvastatin, the %CV of calibration standards ranged from 1.05% to 2.05%, while the %RE ranged from –2.15% to 1.80%. For the analytical batches for orthohydroxy atorvastatin and parahydroxy atorvastatin, the %CV for calibration standards ranged from 2.01% to 6.12% and from 1.43% to 5.65%, respectively. Accuracy (%RE) for the analytical batches for orthohydroxy atorvastatin and parahydroxy atorvastatin ranged from –1.91% to 2.32% and from –1.57% to 4.02%, respectively. The mean correlation coefficients (r²) for atorvastatin, orthohydroxy atorvastatin, and parahydroxy atorvastatin were 0.9997, 0.9983, and 0.9986, respectively.

Analytical Method for Quantification of Istradefylline
Analysis of plasma concentration of istradefylline was performed by Quintiles Inc (now Aptuit Inc, Kansas City, Mo). An HPLC-UV method with UV detection at 360 nm for quantitative determination of istradefylline concentrations in sodium heparin human plasma was used. Using a protein precipitation technique, extracted plasma samples were injected onto the HPLC-UV system and separated by reversed-phase liquid chromatography. The validated method had a standard curve range of 5.00 ng/mL to 2000 ng/mL for istradefylline. The inprocess QC levels of 15.0, 1000, and 1800 ng/mL were used and analyzed at least in duplicate. The regression algorithm was a weighted (1/x) linear regression based on analyte to internal standard peak area ratios. The %CV of calibration standards ranged from 0.1% to 3.1%, while the %RE ranged from –4.0% to 10.6%. For the QC samples, %CV ranged from 4.4% to 7.7%, while the %RE ranged from 2.9% to –1.7%. The regression coefficient for the batch during sample analysis was 0.9996.

Pharmacokinetic and Statistical Analyses
Pharmacokinetic parameters for atorvastatin and its metabolites were estimated through noncompartmental methods, and an ANOVA model (PROC Mixed, version 8.2; SAS Institute, Cary, NC) was used to compare pharmacokinetic parameters for the combination treatment with istradefylline versus those for atorvastatin administration alone. The ANOVA model included terms for subject and treatment. The following parameters were calculated for atorvastatin and its ortho- and parahydroxy metabolites: area under the concentration-time curve from time 0 to infinity (AUC_0-) in ng·h/mL; the observed peak plasma concentration (C_max) in ng/mL; time to peak plasma concentration (T_max) in hours; apparent clearance (CL/F) (for atorvastatin only) in L/h; and terminal half-life (t) in hours. Ninety percent confidence intervals (90% CI) of C_max, and AUC_0- were calculated for the following log-transformed least squares mean (LSM) ratio:

Half-life was compared in a manner similar to that for AUC_0- and C_max but was based on non-log-transformed parameters. A Wilcoxon test was used to test the hypothesis that T_max was the same in the presence and absence of istradefylline. Differences for median T_max were estimated using the original scale.

Because only predose istradefylline concentrations were assessed, formal pharmacokinetic parameter estimation and statistical analysis for istradefylline were not conducted.

Safety Assessments
Safety assessments included vital signs, physical examination, clinical laboratory tests, and 12-lead electrocardiography. Baseline for all safety variables was assessed on day 1 before dosing. Adverse events (AEs) were monitored throughout the study. Treatment-emergent adverse events (TEAEs) were defined as those AEs with onset time at or after the start of study drug or those AEs ongoing at the time of study drug initiation that worsened in severity during the study period. Adverse events with missing start dates were considered TEAEs.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Demographics
Demographic characteristics of the study population are presented in Table I. Twenty male subjects participated in and completed this study. The mean age of all subjects was 42.8 years (range, 21-54).

Peak exposure (C_max), total exposure (AUC_0-), and terminal half-life (t) of atorvastatin were increased in the presence of istradefylline (Table II). Mean atorvastatin C_max was 11.0 ng/mL in the atorvastatin treatment group and 19.4 ng/mL in the combination treatment group. Absorption was rapid; median T_max occurred approximately 2 to 2.5 hours after atorvastatin administration. Atorvastatin t averaged approximately 10 hours when administered alone and approximately 12 hours when administered with istradefylline. Analysis of variance was performed on the natural log-transformed C_max, and AUC_0- of atorvastatin (Table II) and on nontransfomed t. Istradefylline significantly increased the LSM C_max by 53%, LSM AUC_0- by 54%, and LSM t by 27% compared with atorvastatin alone. Median atorvastatin T_max decreased slightly to 2 hours from 2.5 hours. The 90% confidence intervals (CI) for the ratios (atorvastatin plus istradefylline/atorvastatin alone) of AUC_0- and C_max were outside the 80% to 125% bioequivalence window.

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	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Istradefylline, a P-gp and CYP3A inhibitor, has the potential to modulate the systemic exposure of drugs metabolized by CYP3A or are P-gp substrates. Istradefylline had a significant effect on both peak and total systemic exposure of atorvastatin. However, total systemic exposure of the metabolites were not reduced in the presence of istradefylline, suggesting that inhibition of metabolism might not be a major factor contributing to increased systemic exposure of atorvastatin. This becomes clearer when comparing the effects of istradefylline on atorvastatin versus those of itraconazole and grapefruit juice on atorvastatin.

The pharmacokinetic interaction between atorvastatin and istradefylline has similarities, and important differences, when compared with the interactions reported between atorvastatin and either itraconazole or grapefruit juice. Coadministration of a single 40-mg atorvastatin dose in the presence of a 200 mg once-daily steady-state regimen of itraconazole, a potent CYP3A inhibitor, led to a 333% increase in mean atorvastatin AUC_0-, a 20% increase in C_max, and a 290% increase in t compared with administration with placebo.¹⁰ Similarly, coadministration of a single 40-mg atorvastatin dose with grapefruit juice 3 times daily led to a 245% increase in atorvastatin AUC_0-, a 5% increase in C_max, and a 70% increase in t compared with administration with an equal volume of water.¹¹ In the presence of 40-mg once-daily steady-state istradefylline, the increases in atorvastatin AUC_0- and t were 54% and 27%, respectively. In other words, the effect of istradefylline was substantially smaller than that reported for itraconazole or grapefruit juice. The effect of istradefylline on the principal active metabolite of atorvastatin—orthohydroxy atorvastatin—was also different when compared with that of itraconazole or grapefruit juice. Coadministration with itraconazole led to an 82% decrease in C_max, a 17% decrease in AUC_0-, a 200% increase in t, and a 9-hour increase in T_max of orthohydroxy atorvastatin. Similarly, coadministration with grapefruit juice led to a 75% decrease in C_max, a 24% decrease in AUC_0-, an 82% increase in t, and an 8.5-hour increase in T_max of orthohydroxy atorvastatin. These data are consistent with the inhibition of presystemic and systemic metabolism and elimination of atorvastatin by itraconazole and grapefruit juice. In contrast, istradefylline caused a 19% increase in orthohydroxy atorvastatin AUC_0-, a small (5%) decrease in C_max, a nonsignificant increase in t, and no change in T_max. Meanwhile, AUC_0- of parahydroxy atorvastatin was largely unchanged in the presence of istradefylline (increase of 6%), whereas parahydroxy atorvastatin concentrations were below detectable limits in the itraconazole study and were not reported in the grapefruit interaction study. The increase in parent and metabolite concentrations (orthohydroxy atorvastatin) in the presence of istradefylline point to an increased bioavailability of atorvastatin that might be attributed to a predominant presystemic inhibition of P-gp by istradefylline, in contrast to effects of itraconazole. Transporter inhibition by istradefylline is supported by the fact that atorvastatin is a substrate of P-gp,⁷ whereas istradefylline is an inhibitor of P-gp (data on file). The relatively modest pharmacokinetic changes in atorvastatin and its metabolites point to modest P-gp and CYP3A inhibitory effects of istradefylline. Finally, the acid forms of atorvastatin and its metabolites were quantified in this study, whereas the lactone forms were quantified in the itraconazole and grapefruit juice studies. The lactone forms exhibited an extent of interaction similar to that of the acid forms in the itraconazole and grapefruit juice studies, suggesting that the inhibitory effects are comparable between the 2 isoforms.^10,11

View larger version (31K): [in this window] [in a new window]   Figure 1. Mean plasma concentration vs time profiles following administration of atorvastatin alone or in combination with istradefylline. Plasma samples were collected and analyzed for atorvastatin and its metabolites. A, Mean atorvastatin plasma concentration-time profiles. B, Mean orthohydroxy atorvastatin plasma concentration-time profiles. C, Mean parahydroxy atorvastatin plasma concentration-time profiles. QD, daily.

In conclusion, steady-state istradefylline significantly increased peak and total exposure of atorvastatin with little to no suppression of metabolites formed via CYP3A. The pattern of pharmacokinetic interaction observed was consistent with a predominant presystemic effect of istradefylline on P-gp–mediated transport. Overall, coadministration of atorvastatin and istradefylline was safe and well tolerated. Consistent with clinical practice, the dosage of atorvastatin should be individually titrated to clinical response.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The authors thank Kent Allenby, MD, for his review of the manuscript.

Financial disclosure: Niranjan Rao, Neil Sussman, and Helen Wang are employees of Kyowa Pharmaceutical Inc. Barry Dvorchik is a consultant to Kyowa Pharmaceutical Inc. Katsuhiko Yamamoto, Akihisa Mori, and Tatsuo Uchimura are employees of Kyowa Hakko Kogyo Co Ltd. Philip Chaikin was an employee of Kyowa Pharmaceutical Inc at the time this study was conducted.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

1. Kieburtz K. Issues in neuroprotection clinical trials in Parkinson's disease. Neurology. 2006;66(10 suppl 4): S50-S57.[Abstract/Free Full Text]

2. Pinna A, Volpini R, Cristalli G, Morelli M. New adenosine A_2A receptor antagonists: actions on Parkinson's disease models. Eur J Pharmacol. 2005;512: 157-164.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A_2A receptor antagonist treatment of Parkinson's disease. Neurology. 2003;61: 293-296.[Abstract/Free Full Text]

4. Stacy M, and the 6002-US-005/6002-US-006 Clinical Investigator Group. Istradefylline (KW-6002) as adjunctive therapy in patients with advanced Parkinson's disease: a positive safety profile with supporting efficacy. Poster presented at: Movement Disorder Society's 8th International Congress of Parkinson's Disease and Movement Disorders; June 13-17, 2004; Rome, Italy.

5. Hauser RA, Hubble JP, Truong DD, and the Istradefylline US-001 Study Group. Randomized trial of the adenosine A_2A receptor antagonist istradefylline in advanced PD. Neurology. 2003;61: 297-303.[Abstract/Free Full Text]

6. Jacobsen W, Kuhn B, Soldner A, et al. Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos. 2000;28: 1369-1378.[Abstract/Free Full Text]

7. Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42: 1141-1160.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

8. Siedlik PH, Olson SC, Yang B-B, Stern RH. Erythromycin coadministration increases plasma atorvastatin concentrations. J Clin Pharmacol. 1999;39: 501-504.[Abstract]

9. Mazzu AL, Lasseter KC, Shamblen EC, Agarwal V, Lettieri J, Sundaresen P. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther. 2000;68: 391-400.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther. 1998;64: 58-65.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther. 1999;66: 118-127.[Web of Science][Medline] [Order article via Infotrieve]
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This Article Abstract Full Text (PDF) All Versions of this Article: 0091270008320924v1 48/9/1092    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rao, N. Articles by Chaikin, P. Search for Related Content PubMed PubMed Citation Articles by Rao, N. Articles by Chaikin, P. Social Bookmarking                   What's this?