Cytochrome P450 (CYP) enzymes play a role in

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1 Effects of Commonly Administered Agents and Genetics on Nebivolol Pharmacokinetics: Drug Drug Interaction Studies Charles Lindamood, PhD, Stephan Ortiz, PhD, Andrew Shaw, PhD, Russ Rackley, PhD, and J. Christopher Gorski, PhD Drug interactions are a significant clinical concern, particularly in patients with conditions such as heart disease and hypertension, in whom coadministration of multiple drugs is common. Nebivolol is a selective β 1 -blocker with vasodilatory properties approved for the treatment of hypertension. Drug drug interactions were investigated when nebivolol was coadministered to subjects classified as poor CYP2D6 metabolizers and extensive CYP2D6 metabolizers who were receiving other drugs commonly administered to patients with hypertension or compounds metabolized by cytochrome P450 (CYP) 2D6. There were no drug drug interactions when nebivolol was coadministered with hydrochlorothiazide, furosemide, ramipril, losartan, digoxin, or warfarin. Coadministration with fluoxetine (also metabolized by CYP2D6) in extensive CYP2D6 metabolizers impeded the apparent clearance of nebivolol. The authors conclude that nebivolol is safe and well tolerated regardless of genotype and type of medication coadministered. Keywords: Nebivolol; vasodilating; pharmacokinetics; CYP2D6; drug drug interactions; β-blockers Journal of Clinical Pharmacology, 2011;51: The Author(s) Cytochrome P450 (CYP) enzymes play a role in the metabolism of many medications. 1 The CYP2D6 enzyme is involved in the processing of many commonly prescribed drugs, including many β-blockers, selective serotonin reuptake inhibitors, and cardiac drugs. 2 Genetic variability exists in drug metabolism via the CYP pathway. This variability influences patient responses to certain drugs. The majority of people are able to metabolize CYP2D6 substrates extensively and are termed extensive metabolizers (EMs), whereas a minority of the population produces no functional CYP2D6 enzyme and must use an alternative metabolic pathway. 2 These From Toxicology and Clinical Pharmacology, Forest Research Institute, Jersey City, New Jersey (Dr Lindamood, Dr Ortiz); and Pharmacokinetics and Drug Metabolism, Mylan Pharmaceuticals, Morgantown, West Virginia (Dr Shaw, Dr Rackley, Dr Gorski). Submitted for publication September 28, 2009; revised version accepted March 23, Address for correspondence: Charles Lindamood III, Toxicology and Clinical Pharmacology, Forest Research Institute, Harborside Financial Center; Plaza V, Jersey City, NJ 07311; charles.lindamood@frx. com. DOI: / individuals are termed poor metabolizers (PMs). 3,4 In particular, PMs have elevated risk of experiencing adverse drug reactions when multiple drugs are coadministered. CYP metabolism plays an important role in drug drug interactions. Knowledge of CYP genotype may aid in the maintenance of proper CYP enzyme function and the prevention of adverse drug reactions. Nebivolol, a novel vasodilatory, lipophilic β-blocker with the highest β 1 -adrenoceptor selectivity in the β-blocker class, 5 was approved by the US Food and Drug Administration for the treatment of hypertension in December 2007 and is approved in more than 76 other countries outside of North America. Studies have demonstrated that nebivolol is efficacious and well tolerated for the treatment of hypertension. 6,7 One feature that clearly differentiates nebivolol from other vasodilating β-blockers is its endothelium-dependent vasodilatory properties, mediated through the L-arginine/nitric oxide pathway. 8,9 The pharmacokinetics of nebivolol by CYP2D6 genotype have been previously evaluated and reviewed. 15,16 Because complications from hypertension include renal and kidney impairment and CYP J Clin Pharmacol xxxx;xx:x-x 2011;51:

2 LINDAMOOD ET AL metabolism is affected in patients with those conditions, the pharmacokinetics of nebivolol have been evaluated in those subjects. 17,18 Nebivolol consists of a racemic mix of equal proportions of the enantiomers d-nebivolol and l-nebivolol. Both nebivolol isomers are required for optimal blood pressure (BP) lowering. The d isomer has more potent β 1 -blocking activity than does the l isomer, 9,19,20 whereas the l isomer appears to be required for the vasodilating activity of the agent. 9,21,22 After ingestion, nebivolol is rapidly absorbed and undergoes hepatic metabolism through direct N-dealkylation, glucuronidation, and complex aromatic hydroxylation. Dealkylation and hydroxylation involve cytochrome CYP2D6. 22 Because the hydroxylated and glucuronidated metabolites of nebivolol are pharmacologically active, the clinical effects of oral nebivolol are the same for both CYP2D6 genotypes. 22 In plasma, most of the metabolites detected were glucuronides in addition to oxidative N-dealkylated acid. Some oxidative hydroxylated conjugates were detected in the plasma of EMs; however, they were low in the plasma of PMs. In EMs and at doses of 10 mg or less, nebivolol is preferentially β 1 -selective. In PMs and at higher doses, nebivolol inhibits both β 1 - adrenergic receptors and β 2 -adrenergic receptors. 23 As the incidences of hypertension and cardiovascular disease increase, the potential for drug drug interactions with pharmacologic agents used to treat these conditions increases. Therefore, a series of studies were conducted to describe any potential drug drug interactions of nebivolol when coadministered with agents commonly prescribed for patients with hypertension (hydrochlorothiazide [HCTZ], furosemide, ramipril, losartan, digoxin, and warfarin), as well as fluoxetine, which is metabolized by CYP2D6. Methods The clinical portion of these studies was conducted in compliance with the institutional review board and informed consent regulations. CYP2D6 Genotyping Each subject agreed to be genotyped for determination of his or her CYP2D6 metabolite status prior to dosing of study medication. This genotyping tested for the presence of type CYP2D6 *1 and 8 decreaseof-function allelic variants (CYP2D6 *3, CYP2D6 *4, CYP2D6 *5, CYP2D6 *6, CYP2D6 *7, CYP2D6 *8, CYP2D6 *10, and CYP2D6 *17). A subject was classified as an EM if both of the subject s alleles were homozygous for CYP2D6 *1 or heterozygous with 1 of the alleles being CYP2D6 *1. A subject was classified as a PM if both alleles consisted of a decrease-in-function allele variant. At screening, whole blood samples were collected and CYP2D6 genotyping was performed using polymerase chain reaction methods, followed by single nucleotide primer extension reaction (Quest Diagnostics Nichols Institute assay method 10490X, Quest Diagnostics Incorporated-Nichols Institute; San Juan Capistrano, California, USA). Drug Drug Interaction Studies An overview of the drug drug interaction studies is presented in Table I. The open-label studies were conducted in healthy subjects, most of whom were genotyped for PM or EM status. The duration of the studies ranged from 11 to 30 days. Safety data were collected for all the studies (except for furosemide) by recording AEs. In addition to monitoring of AEs, subjects in the losartan study underwent clinical laboratory testing; vital signs and electrocardiograms (ECGs) were also recorded. We assessed safety in the study of nebivolol coadministered with digoxin by performing laboratory tests, and any cardiovascular abnormalities were noted. Bioanalytical Methods d- and l-nebivolol. Plasma levels of d-nebivolol and l-nebivolol, conjugated plus nonconjugated nebivolol, and the other potential interacting drugs in human plasma (heparinized samples) were evaluated. The assay for d-nebivolol and l-nebivolol was linear (range, ). The method developed for the analysis of d-nebivolol and l-nebivolol in human plasma (heparin) was performed using highperformance liquid chromatography with tandem mass spectrometric (HPLC-MS/MS) detection, with a limit of quantification of The conjugated plus nonconjugated nebivolol assay was also linear (range, ), with a limit of quantification of 1.0. Because of the plasma concentration differences of nebivolol in EMs and PMs, 3 different linear standard curve ranges were used in studies in which subjects were genotyped. Standard curve ranges I and III were used for EMs and ranged from 0.02 to 1.5 and 0.04 to 3.0, respectively (limit of quantification of 0.02 and 0.04, respectively). For the PMs, standard curve range II 576 J Clin Pharmacol 2011;51:

3 EFFECTS OF COMMON AGENTS ON NEBIVOLOL PHARMACOKINETICS Table I overview of Drug Drug Interaction Studies Drug Patient Limit of Population Study Design Treatment Regimen a Quantification Linear Additional Details HCTZ capsules (25 mg once daily) Furosemide tablets (40 mg once daily) Ramipril capsules (5 mg once daily) Losartan potassium tablets (50 mg once daily) Healthy subjects (n = 13) 2-group Open-label, study Healthy subjects (n = 12), study Open-label PMs (n = 3) Healthy subjects (n = 12), PMs (n = 3) Healthy subjects (n = 20), PMs (n = 4) Digoxin (Digitek) Healthy subjects (n = 12), tablets (0.25 mg once daily) PM (n = 1) Open-label, randomized, multipledose, 1-period, 2 parallelgroup study Open-label, single-dose, randomized, 2-sequence, 2-treatment, 3-period study Open-label, 1-period, 1-sequence, 2-treatment study Group 1 sequence: Days 1-10, nebivolol Days 11-20, nebivolol + HCTZ Days 21-30, HCTZ Group 2 sequence: Days 1-10, HCTZ Days 11-20, nebivolol + HCTZ Days 21-30, nebivolol Day 1: furosemide Days 2-10: nebivolol Days 8-17: nebivolol plus furosemide Days 1-10: nebivolol or ramipril Days 11-20: nebivolol plus ramipril Days 21-30: nebivolol or ramipril Days 1 and 29: nebivolol or losartan Day 15: nebivolol and losartan Day 1: digoxin loading dose (0.25 mg twice daily) Days 2-7: digoxin Days 8-17: nebivolol plus digoxin SCR II = 0.2 ng/ ml (PMs) SCR III = 0.04 ng/ ml (EMs) SCR II = 0.2 ng/ ml (PMs) SCR III = 0.04 ng/ ml (EMs) Furosemide: 0.05 µg/ml SCR II = 0.2 ng/ ml (PMs) SCR III = 0.04 ng/ ml (EMs) Ramipril/ramiprilat: SCR II = 0.2 ng/ ml (PMs) SCR III = 0.04 ng/ ml (EMs) Losartan: 1.98 ng/ ml EXP-3174: 2.04 SCR II = 0.2 ng/ ml (PMs) SCR III = 0.04 ng/ ml (EMs) Digoxin: Lower and upper limit were and 6.0, respectively SCR II = SCR III = SCR II = SCR III = Furosemide: µg/ml (assayed by CEDRA Corporation, Austin, Tex) SCR II = SCR III = Ramipril/ramiprilat: SCR II = SCR III = SCR II = SCR III = Blood samples were collected on days 1, 8, 9, 18, 19, 28, and 29 (predose); days 10 and 20 (predose and 11 times between 0.25 and 24 h postdose); and day 30 (predose and 14 times between 0.25 and 96 h post dose). Blood samples were collected on day 1 (predose and 13 times between 0.25 and 10 h post dose); days 8 and 9 (predose); day 10 (predose and 16 times between 0.25 and 24 h post dose); and day 11 (predose and 19 times between 0.25 and 96 h post dose). Blood samples were collected on days 10 and 20 (predose and 12 times between 0.25 and 24 h post dose); day 30 (predose and 17 times between 0.25 and 144 h post dose); and prior to the eighth and ninth doses of each treatment period. Blood samples were collected on days 1, 15, and 29 (predose and 21 times between 0.25 and 144 h post dose); they were analyzed for EXP Blood samples were collected on day 7 (predose and 9 times between 0.25 and 24 h post dose) and day 17 (predose and 12 times between 0.25 and 96 h post dose). (continued) Drug Interactions 577

4 LINDAMOOD ET AL Drug Warfarin sodium (Coumadin) tablets (10 mg once daily) Fluoxetine hydrochloride capsules (20 mg once daily) Patient Limit of Population Study Design Treatment Regimen a Quantification Linear Additional Details Healthy subjects Open-label, Days 1 and 17: warfarin Warfarin: (n = 12) 1-period, 1-sequence, 2-treatment study Days 8-22: nebivolol 1.00 Healthy CYP2D6 genotyped subjects (n = 10) Open-label study Day 1: nebivolol Days 8-28: fluoxetine Day 28: nebivolol plus fluoxetine Nebivolol: 0.04 ng/ ml Fluoxetine: Anticoagulation (prothrombin time, INR) was also measured in this study; blood samples were collected on days 1 and 17 (predose and 13 times between 0.25 and 144 h post dose) Blood samples were collected on day 1 (predose and 18 times between 0.25 and 144 h post dose); days 26 and 27 (predose); and day 28 (predose and 18 times between 0.25 and 144 h post dose). CYP2D6, cytochrome P450 2D6; EM, extensive metabolizer; HCTZ, hydrochlorothiazide; INR, international normalized ratio; PM, poor metabolizer; SCR, standard curve range. a. Nebivolol dose = 10 mg once daily. was used, ranging from 0.2 to 15.0 (limit of quantification of 0.2 ). Overall, for standard curve range II, the between-day accuracy varied within 9.4% and 10.4% of the nominal concentration for d-nebivolol and within 9.3% and 10% of the nominal concentration for l-nebivolol. Overall, for standard curve range III, the between-day accuracy varied within 7.0% and 13% of the nominal concentration for d-nebivolol and within 7.6% and 13% of the nominal concentration for l-nebivolol. Hydrochlorothiazide. Analysis of hydrochlorothiazide in human plasma (heparin) was performed using HPLC-MS/MS detection, which had a limit of quantification of 5. The between-day accuracy varied within 1.3% and 1.5% of the nominal concentration. Furosemide. Analysis of furosemide in human plasma (heparin) in this study was performed using HPLC-MS/ MS detection, which had a limit of quantification of 0.05 µg/ml. The assays were linear from 0.05 to 10 µg/ml. The between-day accuracy varied within 4.4% and 6.4% of the nominal concentrations. Ramipril. Analysis of ramipril/ramiprilat in human plasma (heparin) was carried out using HPLC-MS/ MS detection, which had a limit of quantification of for ramipril and ramiprilat. The assay was linear from to 250 for ramipril and ramiprilat. The between-day accuracy varied within 5.9% and 4.0% of the nominal concentration. Digoxin. Analysis of digoxin in human plasma (heparin) in this study was performed using an immunoassay kit (Boehringer Mannheim/Roche Digoxin Pack, Behring Diagnostics, Inc., San Jose, California, USA) with method specific to the Hitachi 704 automated clinical chemistry analyzer. The assay had a lower limit of quantification of ng/ ml and an upper limit of quantification of 6.0 ng/ ml. Warfarin. Analysis of R- and S-warfarin in human plasma (heparin) in this study was performed using HPLC-MS/MS detection, which had a limit of quantification of The assay was linear from 1.00 to The between-day accuracy for R-warfarin varied within 6.9% and 4.0% of the nominal concentrations. The between-day accuracy for S-warfarin varied within 8.3% and 1.2% of the nominal concentration. Losartan. Analysis of losartan and EXP-3174 (losartan carboxy acid) in human heparinized plasma was performed using HPLC-MS/MS detection, which had a limit of quantification of 1.98 for losartan and 2.04 for EXP The assay was linear from 1.98 to for losartan and from 2.04 to for EXP The between-day accuracy was within 3.1% to 3.3% and 1.2% to 2.7% of the nominal concentration of losartan and EXP-3174, respectively. 578 J Clin Pharmacol 2011;51:

5 EFFECTS OF COMMON AGENTS ON NEBIVOLOL PHARMACOKINETICS Fluoxetine. Samples were assayed for fluoxetine and norfluoxetine using an HPLC-MS/MS detection assay, which had a limit of quantification of The assay was linear over the range of to 100. The between-day accuracy for this study was within 7.4% and 5.3% of the nominal concentration of fluoxetine and within 9.5% and 5.8% for norfluoxetine. Pharmacokinetics Nebivolol plasma concentration was estimated using the sum of the individual plasma concentrations of d-nebivolol and l-nebivolol. Individual nebivolol glucuronide plasma concentrations were calculated by subtracting the individual plasma concentrations for d-nebivolol and l-nebivolol from the corresponding conjugated plus nonconjugated nebivolol plasma concentrations. Single-dose and steady-state pharmacokinetic parameters for nebivolol, nebivolol glucuronides, and the potentially interacting drugs were calculated using noncompartmental techniques. For losartan, the pharmacokinetics of the active metabolite EXP-3174 were also examined. For all studies, standard pharmacokinetic calculations were used, which include the following measurements. Maximum concentrations during the steady-state dosing interval (C max ) and the time at which they occurred after dosing ( ) were determined from the observed plasma concentration time profile over the sampling time interval. Area under the plasma drug concentration time curve (AUC τ ) was computed using linear trapezoidal integration. The AUC τ curve from zero to infinity (AUC 0- ) was calculated as the sum of the AUC τ to the time of the last measured concentration at trough (AUC last ) plus the last quantifiable concentration divided by the first-order apparent elimination rate constant (C l /K el ). The first-order apparent elimination rate constant (K el ) was determined as the slope (by linear regression analysis) of the terminal linear phase of the log-transformed plasma concentration time curve. The elimination half-life ( ) was calculated as 0.693/K el. The apparent clearance (CL/F) was calculated as dose/auc τ (where F is the absolute bioavailability of the compound), whereas the apparent volume of distribution (V d /F) was calculated as CL/F K el. To confirm that steady state had been obtained, trough concentrations (C trough ) were reported from plasma concentrations prior to dosing on varying days in the furosemide and HCTZ studies. The average steady-state concentration over the dosing interval (C AV,SS ) was calculated at varying time intervals as (AUC τ )/ τ, where τ is the time between doses. Pharmacodynamics (Used for Warfarin Only) Pharmacodynamic parameters for prothrombin time and international normalized ratio (INR) were calculated using noncompartmental techniques. The maximum concentration for prothrombin time and INR (P and INR max, respectively) and the associated were determined from the observed prothrombin time time or INR time profiles over the sampling time interval. Area under the prothrombin time time or INR time curves (PTAUC or INRAUC 0-144, respectively) was the sum of the linear trapezoidal estimation of the areas from the time of dosing to the time of the last recorded measurement (144 hours). The percentage of unbound warfarin was calculated to assess any effects of nebivolol on warfarin activity. Statistical Methods Statistical analyses were performed on the plasma concentrations, and the pharmacokinetic parameters for the nebivolol analytes were analyzed using the general linear models procedure of SAS software (SAS Institute, Cary, North Carolina, USA) for all of the studies summarized here. The model tested for treatment effects in the parameter means at an α =.05 level. The following pharmacokinetic parameters were analyzed using nontransformed data: C max,,, and CL/F. In some studies, C trough, minimum concentration during the steady-state dosing (C min ), time to minimum concentration (T min ), AUC τ, V d /F, AUC last, and AUC 0- were also determined. Logarithmic (log e ) transformation of the following parameters was used in some studies: lnauc τ, lnc max, lnauc last, lnauc max, and lnauc 0-. Two-sided procedures were used to construct 90% confidence intervals (CIs) for the drug drug interaction studies. Statistical analyses were used for comparisons of treatment-group pharmacokinetic parameters for the renal impairment study. Least squares (LS) means were also calculated for the ratios of test (single-dose) to reference (steady-state) pharmacokinetic parameters in the drug drug interaction studies. Results Drug Drug Interaction Studies Potential pharmacokinetic interactions between nebivolol and agents used to treat heart failure and hypertension and agents metabolized using CYP2D6 were evaluated. Drug Interactions 579

6 LINDAMOOD ET AL Table II Pharmacokinetic Parameters of Nebivolol and Hydrochlorothiazide When Taken Concomitantly and Alone Pharmacokinetic Parameter Nebivolol + HCTZ, LS Means Ratio: (Nebivolol + HCTZ)/ Nebivolol 90% CI d,l-nebivolol C max, 9.7 (149) 11.4 (147) AUC 0-24, ng h/ml 182 (186) 197 (173) C trough, 4.9 (196) 5.4 (179) K el, h (23.3) (38.9), h 16.3 (24) 16.1 (54) CL/F, L/h 585 (86) 523 (85) V d /F, L (62) (103), h a 1.5 ( ) 2.0 ( ) HCTZ C max, (38) (29) AUC 0-24, ng h/ml 1109 (25) 1215 (28) C trough, 10.6 (32) 11.8 (47) K el, h (11) (14), h 9.6 (10) 9.0 (15) CL/F, L/h 24 (21) 22 (25) V d /F, L 323 (28) 286 (30), h a 2.0 ( ) 2.0 ( ) AUC 0-24, area under the plasma concentration time curve over the 24-hour dosing interval; CI, confidence interval; CL/F, apparent oral clearance (CL/F, dose/auc 0-24 ); C max, maximum concentration during the steady-state dosing interval; CV, coefficient of variance; K el, first-order apparent elimination rate constant; HCTZ, hydrochlorothiazide; LS, least squares;, elimination half-life ( = 0.693/K el ); V d /F, apparent volume of distribution (V d /F = [CI/F]/ K el );, time at which C max occurred relative to the administration of the steady-state dose. a. values are presented as median (range). Hydrochlorothiazide. The potential interaction between nebivolol 10 mg once daily and the thiazide diuretic hydrochlorothiazide (HCTZ) 25 mg once daily, used to treat patients with heart failure and hypertension, was evaluated in 16 healthy subjects. Thirteen subjects (10 EMs and 3 PMs) completed the study (11 males, 2 females; age range, years). Among the 13 subjects who received nebivolol and HCTZ, there were no changes in the rate and extent of nebivolol or HCTZ absorption (Table II). Steadystate dosing of nebivolol was safe and well tolerated, with no cardiovascular abnormalities or drug-related changes in laboratory parameters reported. Furosemide. Furosemide 40 mg once daily, another diuretic, was analyzed for potential pharmacokinetic interactions with nebivolol 10 mg once daily. Steadystate plasma concentrations were achieved by day 9 for d-nebivolol and l-nebivolol in the 3 PMs and 12 EMs (7 males, 8 females; age range, years) in this study. Furosemide did not change mean C ss, AUC τ, or CL/F for d-nebivolol or l-nebivolol in either genotype (Table III). No change in nebivolol (in PMs) and C max (in EMs) was observed when nebivolol was coadministered with furosemide. In PMs, ratios of the LS means of the remaining pharmacokinetic parameters were 15% different or less when nebivolol was coadministered with furosemide compared with when nebivolol was taken alone. This could be due to intrasubject variability. Similarly, nebivolol had no effect on the pharmacokinetics of furosemide (data not shown). C max, AUC last, AUC 0-, and CL/F for furosemide were unaltered. Confidence intervals for lnc max, lnauc last, and lnauc 0- were slightly different between treatments, representing at most a 7% decrease in ratios of the LS means for those taking furosemide with nebivolol compared with those taking furosemide alone. The changes in estimated furosemide pharmacokinetic parameters during concomitant administration of furosemide with nebivolol were not considered to be of any clinical relevance. A total of 11 AEs were reported or observed in 6 of the 15 subjects. Eight AEs (73%) were reported as mild in severity, and 3 AEs (27%) were reported as moderate in severity. The most commonly reported AE was headache (55% of all AEs). 580 J Clin Pharmacol 2011;51:

7 EFFECTS OF COMMON AGENTS ON NEBIVOLOL PHARMACOKINETICS Table III Pharmacokinetic Parameters of d,l-nebivolol Taken Concomitantly With Furosemide EMs (n = 12) PMs (n = 3) Pharmacokinetic Parameter Nebivolol, Nebivolol + Furosemide, LS Means Ratio: (Nebivolol + Furosemide)/ Nebivolol 90% CI Nebivolol, Nebivolol + Furosemide, LS Means Ratio: (Nebivolol + Furosemide)/ Nebivolol 90% CI C max, 2.5 (39) 2.4 (25) (11) 43.3 (16) C ss. 0.6 (33) 0.6 (28) (12) 33.2 (18) AUC τ, ng h/ml 15 (33) 14 (28) (12) 797 (18) C trough, (44) 0.2 (39) (14) 23.8 (18) C min, 0.2 (41) 0.2 (39) 23.1 (15) 23.8 (18), h 10.6 (17) 12.3 (46) 32.6 (25) 34.9 (9) CL/F,L/h 757 (30) 746 (25) 14 (12) 13 (17) V d /F,L 11,467 (31) 13,657 (63) 639 (14) 638 (9), h a 1.0 ( ) 1.0 ( ) 4.0 ( ) 6.0 ( ) T min, h 14.0 (88) 10.0 (124) 0.1 (173) 0.0 (n/a) AUC τ, area under the plasma concentration time curve; CI, confidence interval; CL/F, apparent clearance; C max, maximum concentration; C min, minimum concentration during the steady-state dosing interval; C ss, average steady-state concentration over the dosing interval; C trough, drug concentration at trough; CV, coefficient of variance; EM, extensive metabolizer; LS, least squares; PM, poor metabolizer;, elimination half-life;, time to maximum concentration; T min, time to minimum concentration; V d /F, apparent volume of distribution. a. values are presented as median (range). Ramipril. Three PMs and 12 EMs (8 males, 7 females; age range, years) were used to evaluate the potential interaction between nebivolol 10 mg once daily and the angiotensin-converting enzyme inhibitor ramipril 5 mg once daily. When nebivolol was coadministered with ramipril, steady-state plasma concentrations for nebivolol plus ramipril were achieved by day 20 in PMs compared with day 10 in EMs. For ramipril plus nebivolol, or ramipril alone, steady-state plasma concentrations of ramiprilat (the active metabolite of ramipril) were achieved by day 30 in EMs. No treatment differences were observed when ramipril was coadministered with nebivolol, compared with nebivolol alone, in mean C ss, AUC τ,, or CL/F for d-nebivolol or l-nebivolol, in either PMs or EMs. The 90% CIs for log-normalized peak plasma concentrations for d-nebivolol, l-nebivolol, and d,l-nebivolol in both PMs and EMs were slightly greater than 80% to 125%, with up to a 12% decrease observed in ratios of the LS means of C max for nebivolol when coadministered with ramipril. Changes seen with steady-state pharmacokinetic parameters for d-nebivolol or l-nebivolol were most likely due to intrasubject variation (29%) in these data. Nebivolol, when coadministered with ramipril, did not affect any drug elimination parameters in EMs; drug elimination could not be determined in PMs because of the relatively flat plasma nebivolol concentration time profiles. The ramipril data revealed no treatment differences when nebivolol was coadministered with ramipril compared with ramipril alone (Table IV). A total of 58 AEs were reported or observed in 10 of the 15 subjects. The most commonly reported AE was fatigue (22% of all AEs), followed by headache (12% of all AEs) and dizziness (7% of all AEs). No serious or life-threatening AEs were reported for this study. Losartan. Potential interactions between losartan 50 mg once daily, an angiotensin II receptor blocker, and nebivolol 10 mg once daily were evaluated in 24 healthy subjects (20 EMs and 4 PMs). Data were collected for 20 subjects (3 PMs and 17 EMs) in the nebivolol treatment group, 24 subjects (4 PMs and 20 EMs) in the losartan treatment group, and 23 subjects (3 PMs and 20 EMs ) in the losartan plus nebivolol group. The pharmacokinetics of nebivolol in both genotypes did not substantially change when coadministered with losartan. Nebivolol slightly reduced the C max (11%), AUC last (14%), and AUC 0- (14%) of losartan (Table V). However, the disposition of the losartan metabolite EXP-3174, which is responsible for most of the antagonism at angiotensin II receptors, was not appreciably affected by nebivolol (C max, AUC last, and AUC 0- were decreased by 6%, 2%, and 2%, respectively; data not shown). Thus, these changes were not considered clinically Drug Interactions 581

8 LINDAMOOD ET AL Table IV Pharmacokinetic Parameters of Ramipril Coadministered With Nebivolol Mean for Ramipril Mean for Nebivolol + Ramipril All Subjects (n = 15) Pharmacokinetic Parameter EM (n = 12) PM (n = 3) EM (n = 12) PM (n = 3) LS Means Ratio 90% CI AUC τ, ng h/ml C ss, C max, , h a 2.0 ( ) 2.0 ( ) 2.0 ( ) 2.0 ( ), h CL/F, L/h AUC τ, area under the plasma concentration time curve; CI, confidence interval; CL/F, apparent clearance; C max, maximum concentration; C ss, average steady state concentration over the dosing interval; EM, extensive metabolizer; LS, least squares; PM, poor metabolizer;, time at maximum concentration;, elimination half-life. a. values are presented as median (range). Table V Pharmacokinetic Parameters of Losartan Alone and When Administered With Nebivolol Pharmacokinetic Parameter Losartan (n = 24), Nebivolol + Losartan (n = 23), LS Means Ratio: (Nebivolol + Losartan)/ Losartan 90% CI AUC last, ng h/ml 533 (33) 470 (42) AUC 0-, ng h/ml 545 (33) 482 (42) C max, (47) (53) , h a 1.0 ( ) 1.0 ( ) K el, h (24) (27), h 2.5 (25) 2.6 (27) CL/F, L/h 103 (37) 122 (41) V d /F, L 348 (28) 425 (28) AUC last, area under the plasma concentration time curve to the time of the last measured concentration; AUC 0-, area under the plasma concentration time curve from zero to infinity; CI, confidence interval; CL/F, apparent clearance; C max, maximum concentration; CV, coefficient of variance; K el, firstorder apparent elimination rate constant; LS, least squares;, time to maximum concentration;, elimination half-life; V d /F, apparent volume of distribution. a. values are presented as median (range). relevant. Clinical laboratory results, vital signs, and ECG monitoring indicated no safety risk when nebivolol was taken either alone or concomitantly with losartan. A total of 30 AEs were reported by 14 subjects; the majority of events were mild to moderate in severity (21 AEs), with headache being the most common complaint. Digoxin. Thirteen healthy subjects (1 PM and 12 EMs; age range, years) were evaluated for potential interactions between nebivolol 10 mg once daily and digoxin 0.25 mg once daily. Concomitant administration of nebivolol and digoxin resulted in no clinically relevant changes in the pharmacokinetics of digoxin (data not shown). The ratio of C max in the absence of nebivolol to C max in the presence of nebivolol was 1.07 (90% CI, ), and the ratio for AUC τ was 1.08 (90% CI, ). A total of 14 AEs were experienced by 6 subjects; all events were mild in severity, except 1 report of a moderately stiff neck. At steady-state dosing, there was no evidence of cardiovascular abnormalities or drug-related clinical laboratory test result abnormalities. There were no deaths or serious AEs in this trial. Warfarin. Because the anticoagulant warfarin is known to be involved in numerous drug interactions and is commonly prescribed to hypertensive patients, the potential interaction of nebivolol 10 mg once daily with warfarin 10 mg once daily was evaluated. Data from 12 subjects (age range, years) were included in the analysis. Administration 582 J Clin Pharmacol 2011;51:

9 EFFECTS OF COMMON AGENTS ON NEBIVOLOL PHARMACOKINETICS Table VI Anticoagulant Activity of Warfarin Alone and Following Nebivolol Coadministration Pharmacokinetic Parameter Warfarin (n = 12), Warfarin + Nebivolol (n = 12), LS Means Ratio: (Warfarin + Nebivolol)/ Warfarin 90% CI P, s 13 (12) 12 (7.9) PTAUC 0-144, s h 1680 (7.6) 1636 (4.9) , h a 24.0 ( ) 24.0 ( ) INR max 1.3 (12) 1.2 (9.4) INRAUC 0-144, h 161 (7.7) 156 (4.9) CI, confidence interval; CV, coefficient of variance; INR max, maximum concentration for international normalized ratio time; INRAUC 0-144, area under the international normalized ratio time curve; LS, least squares; P, maximum concentration for prothrombin time; PTAUC 0-144, area under the prothrombin time curve;, time to maximum concentration. a. values are presented as median (range). Table VII Pharmacokinetic Parameters of d,l-nebivolol Administered Alone and Coadministered With Fluoxetine Pharmacokinetic Parameter Nebivolol a (n = 24), Nebivolol + Fluoxetine b (n = 23), LS Means Ratio: (Nebivolol + Fluoxetine)/ Nebivolol 90% CI AUC last, ng h/ml 13 (34) 90 (62) 6.3 a c AUC 0-, ng h/ml 14 (32) 92 (63) 6.0 a c C max, 2.3 (26) 5.5 (34) 2.8 a c, h d 1.0 ( ) 2.5 ( ) K el, h (22) (36) , h 12.5 (22) 17.5 (48) CL/F, L/h 787 (31) 143 (54) V d /F, L (33) 3066 (37) AUC last, area under the plasma concentration time curve to the time of the last measured concentration; AUC 0-, area under the plasma concentration time curve from zero to infinity; CI, confidence interval; CL/F, apparent clearance; C max, maximum concentration; CV, coefficient of variance; K el, firstorder apparent elimination rate constant; LS, least squares;, time to maximum concentration;, elimination half-life; V d /F, apparent volume of distribution. a. Nebivolol 10 mg alone on day 1. b. Nebivolol plus fluoxetine 20 mg on day 28. c. Natural log-transformed parameters were used. d. values are presented as median (range). of nebivolol resulted in no statistically significant changes in the pharmacokinetics of warfarin. Nebivolol also had no significant effects on the anticoagulant activity of warfarin, as assessed by prothrombin time and INR profiles from 0 to 144 hours after warfarin dosing (Table VI). A total of 3 subjects experienced 4 AEs; all events were mild in severity and were considered to be possibly related to study medication. There was 1 report each of periodic shakiness, periodic fatigue, headache, and nausea. All AEs occurred during nebivolol dosing, except for 1 headache that was reported on day 17 dosing of warfarin and nebivolol. There were no deaths or serious AEs in this trial. Fluoxetine. Fluoxetine is a strong inhibitor of CYP2D6; therefore, it was of clinical importance to evaluate potential interactions between nebivolol 10 mg once daily and fluoxetine 20 mg once daily. A total of 10 EMs (age range, years) completed the study. Steady-state conditions had been achieved for both fluoxetine and norfluoxetine analytes after 21 consecutive days of fluoxetine administration (data not shown). In all subjects, coadministration of fluoxetine increased the plasma concentrations of each nebivolol analyte (Figure 1). Steady-state coadministration of fluoxetine reduced the apparent clearance of nebivolol from the body, leading to increased C max and AUC 0- values of approximately 2.3-fold and 6-fold higher, Drug Interactions 583

10 LINDAMOOD ET AL Figure 1. Mean plasma concentration time curves for (A) d-nebivolol, (B) l-nebivolol, and (C) d,l-nebivolol when given alone or when coadministered with fluoxetine. respectively, than when fluoxetine was not coadministered (Table VII). However, the elevated plasma concentrations of nebivolol observed when given with fluoxetine were considerably lower than the clinically safe and well-tolerated levels of nebivolol alone, previously observed in PMs (AUC 0-, 614 ng h/ml; C max, 9.2 ). 19,20 A total of 9 AEs were experienced by 3 subjects. All AEs were considered mild in severity. Five of the AEs (56%) were considered to be drug related. No AEs were reported in subjects receiving nebivolol alone; 3 events were reported when fluoxetine was administered alone (observed somnolence, feet swelling, sleeplessness) and 6 when nebivolol was coadministered with fluoxetine (2 reports of headache and 1 each of lightheadedness, nausea, occasional vomiting, and occasional loose stools). None of the AEs in this study were serious or life-threatening. Discussion Because the pathophysiology of hypertension is multifactorial, combination regimens that target different BP-lowering mechanisms and associated compensatory responses may be useful in achieving target BP goals Consequently, and in line with various hypertension treatment guidelines, patients with hypertension are likely to take several classes of medication concomitantly Therefore, it is important to assess potential drug drug interactions associated with the use of novel therapies, such as nebivolol. The coadministration of nebivolol (10 mg) with the antihypertensive medications hydrochlorothiazide, furosemide, ramipril, and losartan did not change the pharmacokinetics of any of these drugs. This study supports previous findings 29 that have demonstrated a lack of drug drug interactions between nebivolol and these agents and indicates that nebivolol can be used safely with most drug classes commonly used in the treatment of hypertension. Both warfarin and digoxin are medications commonly taken by patients with cardiovascular disease and thus are often used in combination with antihypertensive agents. In this study, coadministration of neither warfarin nor digoxin altered the pharmacokinetics of nebivolol. There was no change in the pharmacodynamics and anticoagulation activity of warfarin when coadministered with nebivolol. The lack of interaction of nebivolol when given with warfarin and digoxin confirms reports from earlier studies in healthy subjects, in which no interactions were seen for either drugs. 29 The steady-state pharmacokinetic data for nebivolol when administered with digoxin were also comparable to data previously obtained from a multiple-dose study in healthy EMs and PMs. 12 However, caution should be used when prescribing nebivolol with agents that reduce heart rate, such as digoxin. 23,29 Coadministration of nebivolol with other medications commonly prescribed in hypertensive patients did not cause any safety concerns in PMs or EMs, and there were no cardiac effects when nebivolol and digoxin were given concomitantly. When nebivolol was coadministered with fluoxetine, the C max and AUC 0- values for nebivolol in PMs and EMs were reduced approximately 6 times and 2 to 3 times, respectively. Because of the elevation in plasma concentrations of nebivolol when taken with fluoxetine or with other CYP2D6 inhibitors, caution should be taken when these agents are coadministered with nebivolol. Because nebivolol dosing should be individualized to the needs of the patient, patients should be closely monitored and nebivolol dose adjusted according to blood pressure response. 23 Nebivolol did not alter the pharmacokinetics of frequently prescribed medications used to treat hypertensive patients, nor did frequently prescribed medications affect the pharmacokinetics of nebivolol. Nebivolol is safe and well tolerated regardless of genotype and type of medication coadministered. 584 J Clin Pharmacol 2011;51:

11 EFFECTS OF COMMON AGENTS ON NEBIVOLOL PHARMACOKINETICS Financial disclosure: These studies were funded by Forest Laboratories and Mylan Pharmaceuticals. The authors acknowledge Strategic Medical Initiatives and Camargo Pharmaceutical Services for editorial support, which was funded by Forest Laboratories. Dr Lindamood and Dr Ortiz are employees of Forest Research Institute, a subsidiary of Forest Laboratories. Dr Shaw, Dr Gorski, and Dr Rackley are employees of Mylan Pharmaceuticals. References 1. Wijnen PA, Op den Buijsch RA, Drent M, et al. Review article: the prevalence and clinical relevance of cytochrome P450 polymorphisms. Aliment Pharmacol Ther. 2007;26(suppl 2): Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76: Evans WE, Relling MV, Rahman A, McLeod HL, Scott EP, Lin JS. Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans. 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