Abstract Introduction Objectives Methods

ABSTRACT Table 3. Summary of Drug Interaction Evaluation Lack of Significant Drug Interactions for Sumanirole in Phase II Studies Using PURPOSE: Sumanirole is a highly D -selective dopamine 2 Number of Number of receptor agonist that is in development for the treatment of Population Pharmacokinetic Methods Subjects Observations Parkinson's disease (PD). Metabolism of sumanirole and in Change on With vitro data indicate that clinically significant pharmacokinetic in Mean % of the Univariate Concomit- Concomit- (PK) drug-drug interactions are unlikely. This was further Joel S. Owen, PhD1, Kathryn Liolios, MA1, Gwyn A. D'Souza, PhD2, Barbara J. Carel, MS3 Drug CL/F SEM P Value ant Drug ant Drug investigated using population pharmacokinetic (PPK) 1 2 Amantadine 0.434 440.1 0.629 71 407 methodology. Cognigen Corporation, Buffalo, NY, USA; Pharmacia Corporation, High Wycombe, UK; 3Pharmacia Corporation, Kalamazoo, MI, USA Aspirin 0.601 196.3 0.349 77 496 METHODS: Data were obtained from 2 double-blind, placebo- β-Blockers* 2.22 154.1 0.066 22 144 controlled trials of sumanirole alone in early PD and sumanirole with levodopa in advanced PD. Patients received twice- Hypotensive † daily extended-release oral sumanirole doses ranging from 2 agents 0.0943 1124.1 0.882 128 815 to 48 mg/d. A one-compartment PPK model, with creatinine Levodopa‡ 0.907 100.0 0.281 111 200 clearance (CrCL) and gender as covariates of clearance Organic anion (CL/F), was used in NONMEM® to characterize the influence METHODS Figure 1. Sumanirole concentrations versus time transport of concomitantly administered drugs on sumanirole PK. Use since last dose for all dose groups. Figure 3. CRF for drug-iinteraction assessment inhibitors§ 0.450 251.1 0.462 86 549 of a specialized case report form (CRF) page streamlined Population Pharmacokinetic Model and Drug Interaction Assessment construction of the drug-interaction analysis dataset. Data 250 Organic anion Various single agents and classes of compounds were eval- transport Data were pooled from 2 Phase II trials. Data from 1 Phase I trial substrates|| 0.797 204.5 0.336 83 465 uated as a linear shift to the CL/F model. Univariate forward were also included for model development. 200 selection (α=0.05) was followed by backward elimination Sampling design: Study 009—5 to 6 blood samples obtained after Organic cation (α=0.001). dose at Visit 8, 1 sample at Visit 9, and 1 (217 subjects) or 9 (50 transport subjects) samples at Visit 11; Study 010—single blood samples at 150 Visits 9 and 11; Study 020—full profile (13 samples) after 5 days inhibitors¶ -0.172 1866.3 0.938 7 47 RESULTS: PPK data included 378 patients and 20 healthy Pharmacostatistical Model 100 Organic cation subjects. Levodopa coadministration occurred in 111 sub- transport NONMEM®, version 5.1.1 jects (200 sumanirole concentrations) and was absent for substrates# 1.77 123.7 0.067 35 237 287 subjects (2394 concentrations in early PD patients). PK model: one-compartment model with first-order absorption and 50 elimination Renal anions** 1.06 106.6 0.059 150 906 Levodopa did not significantly (P=0.281) influence sumani- PNU-95666 Concetration (ng/mL) Interindividual error determined by the exponential error model role PPK (<5% increase in mean CL/F). Selegiline was coad- 0 Renal cations†† 1.51 127.2 0.093 42 284 Residual variability determined with the proportional error model 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 ministered in 85 subjects and had an effect, but this did not Creatinine clearance (CrCL) and gender were included as Time Since Last Dose (h) Selegiline -2.09 32.7 0.011 85 540 reach statistical significance (P<0.001). The magnitude of the significant covariates of clearance (CL/F) Dose 1 mg 2 mg 4 mg 8 mg effect was small accounting for only a 10% decrease in CL/F 16 mg 24 mg 32 mg 48 mg Trihexyphenidyl -0.446 287 0.725 36 187 CrCL estimated using the modified Cockcroft and Gault method1 for a patient with average CrCL. Other compounds and class- β− β * blockers included: propranolol and metoprolol. es investigated, such as amantadine, aspirin, -blockers, Drug-Interaction Assessment † Hypotensive agents included: diltiazem, furosemide, hydrochlorothiazide, metoprolol, hypotensive agents, organic anion and cation transport sub- nifedipine, propranolol, selegiline, triamterene, trimethoprim, and verapamil. A specialized case report form (CRF) page was used to efficiently ‡ strates and inhibitors, renal anions, renal cations, and tri- Interaction for levodopa assumes all Study 010 subjects/concentrations had concomitant construct the drug-interaction analysis dataset (Figure 3). levodopa and no Study 009 or 020 subject concentrations had concomitant levodopa. hexyphenidyl, did not significantly alter sumanirole PK. Single agents and classes of concomitant medications evaluated § Organic anion transport (OAT) inhibitors included: aspirin, furosemide, indomethacin, and as a linear shift to the CL/F model verapamil. Table 1. Studies Included in the Population CONCLUSION: Sumanirole is not susceptible to drug inter- Univariate forward selection analyses performed, followed by || Organic anion transport substrates included: amantadine, ampicillin, cephalexin, Analyses cimetidine, and hydrochlorothiazide. actions based on these PPK data. No single agent, including stepwise backward elimination ¶Organic cation transport (OCT) inhibitors included: cimetidine and verapamil. Statistical Analyses Treatment levodopa, or class of compounds studied, significantly Protocol Study Design Regimen # Organic cation transport substrates included: metoprolol, propranolol triamterene, trimethoprim, and ranitidine. altered sumanirole PK. Statistical significance: univariate forward-selection analyses: M/2760/0009 Double-blind, placebo-controlled, Dose escalating up **Renal anions included the combined list of OAT substrates and OAT inhibitors. P=0.05; backward elimination: P=0.001 dose-response study of sumanirole to groups: 0 mg †† Renal cations included the combined list of OCT substrates and OCT inhibitors. ® tolerability, safety, and efficacy in (placebo), 2, 8, 24 Goodness-of-fit of each NONMEM analysis assessed by patients with early PD or 48 mg/d examination of: INTRODUCTION M/2760/0010 Safety, tolerance, and efficacy Dose escalating to z Scatterplots of predicted vs measured concentrations and vs weighted residuals evaluation of sumanirole as an any of 1, 2, 4, 8, 16, For many years, the mainstay of treatment for Parkinson's adjuvant to levodopa in advanced PD 24, 32, or 48 mg/d z %SEMs of the parameter estimates disease (PD) has consisted of dopamine replacement therapy; 666E-CNS- A single-blind, placebo-controlled, Multiple-dose (twice z Changes in the estimates of the interindividual and residual however, the occurrence of late side effects in patients on variability 0075-020 randomized parallel group and daily) administration CONCLUSIONS long-term levodopa prompted a search for novel crossover study to investigate of placebo, 1-mg, Table 2. Predicted Parameter Estimates from the Final Pharmacokinetic Model antiparkinsonian drugs. pharmacokinetics and adverse event or 2-mg doses The population pharmacokinetics of sumanirole were best profile of sumanirole given in an Parameter Population Mean %SEM* RESULTS extended release formulation to described using a one-compartment model with first-order Sumanirole (PNU-95666E), a selective D2-receptor agonist Estimate Caucasian healthy volunteers absorption and elimination. within the D2-receptor family, is currently in development. † Population Pharmacokinetic Model and Drug Interactions CL/F coefficient (L/h) 20.1 2.8% Because of its selectivity for the D2 subtype, sumanirole is † This population analysis indicates that sumanirole is not predicted to have fewer side effects than other dopaminergic Power for CrCL effect on CL/F 0.622 10.0% susceptible to PK drug-drug interactions and confirms previous agents used in the treatment of PD. Data were collected from 398 subjects: 111 subjects were CL/F shift for males† (1/h) 2.96 27.6% observations. coadministered levodopa (200 sumanirole concentration samples); Because sumanirole undergoes both renal excretion of Figure 2. Individual predicted sumanirole concen- V/F (L) 300 Fixed unchanged drug and metabolism via multiple pathways, drug- 287 subjects received sumanirole monotherapy (2394 trations vs measured sumanirole No single agent, including levodopa, nor pharmacologic class of ka (1/h) 0.379 4.6% drug interactions are unlikely. In vitro data support the hypothesis concentration samples) (Table 1, Figure 1). concentrations. medications explored, significantly (P<0.001) altered that clinically important pharmacokinetic (PK) drug-drug IIV‡ CL/F (%CV) 32.6% 12.3% 300 sumanirole PK. interactions are not anticipated. A one-compartment model with first-order absorption was used to IIV‡ ka (%CV) 39.1% 30.8% 250 This Poster further describes the disposition of sumanirole based describe the data (Table 2; Figure 2). Residual variability (%CV) 21.1% 7.7% on population pharmacokinetic (PPK) analyses and subsequent assessment of the potential for drug-drug interactions. 200 * % SEM = Standard error of the estimate divided by the population mean estimate times Volume of distribution (V/F) was fixed to a constant 300 L because 100%, a measure of the relative precision of estimates REFERENCE θ 2 CrCL 0.622 † CrCL η η of correlation with the absorption-rate constant. 150 CL F = θ • ()+θ • SEXM ∗e 1 = 20.1• ()+ 2.96 • SEXM ∗e 1 1 75.8

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