By He, Yan-Ling Sabo, Ron; Riviere, Gilles-Jacques; Sunkara, Gangadhar; Et al
Key words: Drug interaction – International normalized ratio – Pharmacokinetics – Prothrombin time – Vildagliptin – Warfarin ABSTRACT
Objective: Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha and beta-cell responsiveness to glucose. This study assessed the effect of multiple doses of Vildagliptin 100mg once daily on warfarin pharmacokinetics and pharmacodynamics following a single 25 mg oral dose of warfarin sodium.
Research design and methods: Open-label, randomized, two-period, two-treatment crossover study in 16 healthy subjects.
Results: The geometric mean ratios (co-administration vs. administration alone) and 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) of Vildagliptin, R- and S-warfarin were 1.04 (0.98, 1.11), 1.00 (0.95, 1.04) and 0.97 (0.93, 1.01), respectively. The 90% CI of the ratios for Vildagliptin, R- and S-warfarin maximum plasma concentration (C^sub max^ were also within the equivalence range 0.80-1.25. Geometric mean ratios (co-administration vs. warfarin alone) of the maximum value and AUC for prothrombin time (PT^sub max^, 1.00 [90% CI 0.97, 1.04]; AUC^sub PT^, 0.99 [0.97, 1.01]) and international normalized ratios (INR^sub max^, 1.01 [0.98, 1.05]; AUC^sub INR^, 0.99 [0.97, 1.01]) were near unity with the 90% CI within the range 0.80-1.25. Vildagliptin was well tolerated alone or co-administered with warfarin; only one adverse event (upper respiratory tract infection in a subject receiving warfarin alone) was reported, which was judged not to be related to study medication.
Conclusions: Co-administration of warfarin with vildagliptin did not alter the pharmacokinetics and pharmacodynamics of R- or S- warfarin. The pharmacokinetics of vildagliptin were not affected by warfarin. No dosage adjustment of either warfarin or vildagliptin is necessary when these drugs are co-medicated.
Vildagliptin is an orally active, potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4), the enzyme responsible for the degradation and inactivation of the incretin hormones, glucagon- like peptide-1 (GLP-I) and glucose-dependent insulinotropic peptide (GIP)1. Vildagliptin increases post-prandial levels of intact, biologically active GLP-I and GIP by selectively and reversibly inhibiting DPP-4. Clinical studies in patients with type 2 diabetes mellitus have shown that vildagliptin treatment improves glycemie control2’3 and pancreatic beta-cell function4’5.
Vildagliptin is rapidly and almost completely absorbed following oral administration in humans. Vildagliptin exhibits linear pharmacokinetics with an elimination half-life of about 3 hours after oral administration. The pharmacodynamic half-life, reflected by the mean residence time of DPP-4 inhibition after administration of a single lOOmg oral dose, was 9.6 hours, allowing once daily administration. Metabolism is the primary elimination pathway for vildagliptin in humans, accounting for approximately two-thirds of the elimination of an oral dose. The predominant metabolic pathway of vildagliptin is hydrolysis at the cyano moiety to form a carboxylic acid (LAYl 51) which is pharmacologically inactive. Renal clearance of unchanged vildagliptin accounts for about one-third of total body clearance of the drug. In vitro experiments assessing the activity of a range of cytochrome P450 (CYP450) isoenzymes in human liver microsomes showed no inhibitory effects (IC^sub 50^ values [mu]mol/L) and no quantifiable metabolism of vildagliptin by CYP450 (Novartis, data on file). These results indicate that pharmacokinetic interactions with vildagliptin due to effects on CYP450 isoenzymes are unlikely.
Warfarin is a vitamin K antagonist widely used for the long-term prevention of thrombosis6. Prothrombin time (PT) is the most commonly used parameter to measure the anticoagulant effect of warfarin. An increase in PT results from a reduction of three of the four vitamin K-dependent procoagulant clotting factors (factors II, VII and X) by warfarin, which occurs gradually7. Standardization of PT across studies is achieved by calculation of the international normalized ratio (INR)8; which provides a more reliable measure of blood coagulation than the non-standardized PT ratio9. Warfarin has a narrow therapeutic index with large inter- and intra-individual variations in dose response, necessitating regular determinations of PT to monitor the anticoagulant effect and reduce the risk of bleeding10. Warfarin is a racemic compound; the S-enantiomer has approximately five times greater anticoagulant activity than the R- enantiomer”. Metabolism of R-warfarin is mediated by P450 isoenzyme 3A412, and that of S-warfarin occurs primarily through CYP2C9- mediated hydroxylation12’13. The most common cause of pharmacokinetic interaction with warfarin is inhibition of CYP2C9, leading to an increased concentration of S-warfarin and an increased anticoagulant effect and risk of hemorrhage14.
Based on the known pharmacokinetics and mechanism of action of vildagliptin, pharmacokinetic or pharmacodynamic interactions with warfarin would not be anticipated. The objective of this study was to confirm the lack of any potential drug-drug interaction when warfarin is co-administered with vildagliptin.
Patients and methods
This study enrolled male or female subjects ages 18-45 years in good health, as determined from medical history, physical examination, vital signs, electrocardiogram (ECG), and laboratory tests, including a normal PT. Subjects had a body weight of at least 50kg and were within +-20% of normal for their height and frame size according to the Metropolitan Life Insurance Tables.
Subjects were excluded if they had any condition that would represent a contra-indication for the use of an anticoagulant or history of abnormal bleeding. Other exclusion criteria included smoking (use of tobacco product in the previous 3 months and/or urine cotinine > 500 ng/mL), clinically significant ECG abnormalities or abnormal laboratory values, and any condition that might significantly alter the absorption, distribution, metabolism or excretion of study drugs. Subjects were also excluded if they were vegetarian or ate large amounts of leafy green vegetables (as a high dietary intake of vitamin K could influence the pharmacodynamics of vitamin K antagonists such as warfarin), or if they had used any prescription drugs in the 4 weeks prior to dosing or any over-the-counter medication (except acetaminophen) during the 2 weeks prior to dosing.
Study participants were not permitted to engage in strenuous physical exercise for 7 days before dosing, or take alcohol for 72 hours before dosing until after the study completion evaluation. Intake of xanthinecontaining food or beverages was discontinued 48 hours before dosing and was not permitted while subjects were admitted to the study center.
The study was performed in compliance with the Guidelines for Good Clinical Practice and the Declaration of Helsinki of the World Medical Association and received approval by the Western Institutional Review Board (Olympia, WA1 USA). All participants provided written informed consent prior to study participation.
This was a single-center, open-label, randomized, two-period, two- treatment crossover study. Subject eligibility for the study was assessed based on inclusion and exclusion criteria, safety evaluations and normal PT during a 21-day screening period.
All subjects who met inclusion criteria at screening were admitted to the study center. Following Period 1 baseline evaluations (day-1), subjects were randomized to one of two treatment sequences. Randomization was performed by Novartis Drug Supply Management using a validated system. Subjects assigned to the first treatment sequence received open-label vildagliptin lOOmg once daily for 6 days, co-administered with a single 25 mg oral dose of warfarin sodium on day 2 (Period 1). After a washout period of at least 14 days, subjects then received placebo (matching vildagliptin) once daily for 6 days, with co-administration of warfarin on day 2 (Period 2). Subjects assigned to the second treatment sequence received treatments in the opposite order.
Subjects were admitted to the study center for 9 days and were discharged following the final pharmacokinetic and safety assessments of Period 1. Following the washout period, subjects were readmitted to the study center for Period 2, which was performed in an identical fashion to Period 1 ; end-ofstudy evaluations were performed on the last day of Period 2, after which subjects were discharged.
Study treatments were administered as tablets with 24OmL of water between 7:00am and 8:30am, following an overnight fast of at least 10 hours. On days 1 and 2 of each treatment period, subjects continued to fast until 4 hours post-dose; on days 3-6, subjects were provided with breakfast 30 minutes after dosing.
Blood samples for determination of plasma vildagliptin concentrations were taken pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose on days 1 and 2 of the appropriate treatment period for easubject. Samples for determination of plasma R- and S-warfarin concentrations were taken pre-dose and at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60, 72, 96, 12, 144, and 168 hours post-dose on day 2 of both treatment periods. Blood samples (1 mL for vildagliptin and 5 mL for warfarin) were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein, and collected into a sodium heparin tube. Within 15 minutes, samples for analysis of vildagliptin were centrifuged at between 3 and 5[degrees]C for 15 minutes at approximately 2500rpm, and plasma samples were frozen at – 70[degrees]C or below until analysis was performed. Determination of plasma drug concentrations
Plasma concentrations of vildagliptin were measured by a high- performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) method. The assay consisted of a liquid-solid extraction on Oasis HLB 96-well extraction plates (Waters Corporation, Milford, MA, USA) using an automated system, followed by HPLC using a XTerra MS CIS 5[mu]m column (Waters Corporation, Milford, MA, USA) with isocratic elution using 40% mobile phase A (lOmmol/L ammonium acetate [adjusted to pH 8 with ammonia solution]-methanol [95:5, v/ v]) and 60% mobile phase B (acetonitrile-methanol [10:90, v/v]). Detection was performed by MS/MS with Electro Spray lonization (ESI) using an API 3000 (Applied Biosystems, Foster City, CA, USA) mass spectrometer in positive ion mode. The masses for vildagliptin were precursor ion m/z 304 and product ion m/z 154. The lower limit of quantification for the assay was 2.0ng/mL. The internal standard for this assay was [^sup 13^C^sub 5^^sup 15^N]vildagliptin. Within- study assay validation at nominal vildagliptin concentrations of 5.25, 400 and 900ng/mL showed an assay precision (coefficient of variation) of 5.8-14.5% and a bias of 2.5-4.0%.
Plasma concentrations of R- and S-warfarin were measured by HPLC and fluorescence by CEPHAC EUROPE (Saint Benoit, France). The assay consisted of liquid-liquid extraction with hexane/methylene chloride followed by reverse phase HPLC using a Chiral-AGP column (Chromtech AB, Sollentuna, Sweden) with isocratic elution using phosphate buffer (pH 7.3)/2-propanol. Detection was performed by fluorescence using a Fluorimeter 474 (Waters Corporation, Milford, MA, USA) with lambda^sub exc^ 292 nm and lambda^sub em^ 380nm. The internal standard for the assay was diclofenac sodium. The lower limit of quantification for the assay was lOng/mL. Within-study assay validation at nominal concentrations of 20, 1000, and 1600ng/mL showed an assay precision (coefficient of variation) of 3.1-9.9% for R-warfarin and 2.8-5.5% for S-warfarin, and a bias of 0.0-9.0% for R- warfarin and 0.6 to 10.0% for S-warfarin.
In previous drug-drug interaction studies conducted with warfarin (administered as a single 25 or 30 mg oral dose) and employing a crossover design, the ranges of intra-subject coefficients of variation (CV) for the area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (C^sub max^) for R-warfarin were 0.06-0.15 and 0.07-0.19, respectively, and for S- warfarin AUC and C^sub max^, 0.09-0.19 and 0.08-0.16, respectively15″17. The criterion used to evaluate the significance of a drug interaction was based on the 90% confidence intervals (CIs) for the ratio of geometric means of AUC and C^sub max^ CIs contained within the equivalence range of 0.80-1.25 for both warfarin enantiomers were taken as evidence for no significant interaction. Based on an intra-subject CV of 0.1, a sample size of 16 subjects provided at least 90% power to establish bioequivalence of warfarin administered alone or in combination with vildagliptin.
Pharmacokinetic parameters determined for vildagliptin, R-, and S- warfarin were the AUC extrapolated to infinity (AUC^sub 0^_), C^sub max^, and time at which C^sub max^ occurred (t^sub max^), apparent total plasma clearance (CL/F), and terminal elimination half-life (t^sub 1/2^. The AUC was also calculated between O and 24 hours for vildagliptin (AUC^sub 0-24h^) and between O and 168 hours for warfarin (AUC^sub 0-168h^). Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin Pro (Version 4.0, Pharsight Corp, Mountain View, CA, USA).
Statistical comparisons of log-transformed AUC and C^sub max^ values were performed using an analysis of variance (ANOVA) model (PROC MIXED SAS procedure, SAS Institute Inc., Gary, NC, USA), with sequence, period and treatment as sources of variation and subject (sequence) as random effect. Ratios of geometric mean AUC and C^sub max^ and the associated 90% CIs and p-values for co-administration of vildagliptin and warfarin compared with vildagliptin or warfarin administered alone were calculated using the above model.
The anticoagulant effect of warfarin was assessed by measurement of the PT from blood samples taken at intervals up to 168 hours post- dose. Measurements of prothrombin times were performed on a Sysmex CAl 500 using DATE BEHRING INNOVIN reagent (Lab Corporation of America, Hollywood, FL, USA).
Pharmacodynamic variables were obtained from collected PT values, expressed in seconds, and the INR in INR units. Pharmacodynamic parameters were determined from both the original PT/INR data and change from pre-dose (calculated as the difference between PT/INR obtained at each time point minus prothrombin time obtained at pre- dose). The following pharmacodynamic parameters were determined using non-compartmental methods: the area under the PT-time curve from O to 168 hours (AUC^sub PT^), the peak PT reached (PT ), the area under the INR-time curve from O to 168 hours in international normalized ratio units (AUC^sub INR^), and the peak INR (INR^sub max^).
Statistical comparisons of pharmacodynamic parameters following administration of a single dose of warfarin alone or in combination with vildagliptin were performed using an ANOVA model with sequence, period and treatment as fixed effects and subject (sequence) as random effect. Ratios of geometric means for the pharmacodynamic parameters of warfarin (PT^sub max^, AUC^sub PT^, INR^sub max^ and AUC^sub INR^ and the associated 90% CIs and p-values for co- administration of vildagliptin and warfarin compared with warfarin administered alone were calculated using SAS MIXED.
Safety and tolerability assessments
Safety and tolerability assessments were conducted in all subjects, and included the monitoring and recording of all adverse events (AEs) as well as details of concomitant medications or significant non-drug therapies.
Evaluation of routine blood chemistries, hematologie profile and urine analysis, as well as a physical examination, ECG recordings, and monitoring of vital signs, were performed at screening, baseline, and after the completion of the study.
A total of 16 subjects were enrolled and 15 completed the study; one subject withdrew consent after completion of Period 1 and was not replaced. Subjects had a mean age of 31.9 +- 9.6 years, a mean body weight of 70.2 +- 11.7kg and height of 166 +- 11 cm; there were 10 men and six women. Most subjects (15/16) were of white Hispanic or black Hispanic origin.
Pharmacokinetics of vildagliptin
The plasma concentration-time profiles of vildagliptin were similar, and the pharmacokinetic parameters unaffected, by co- administration of a single 25 mg oral dose of warfarin (Figure 1, Table 1). Ratios of geometric mean values were near unity with the 90% CIs being contained within the bioequivalence range of 0.80- 1.25 for vildagliptin Cmax (geometric mean ratio 1.01 [90% CI 0.89, 1.14]) and AUC^sub 0-24h^, (mean ratio 1.04 [0.98, 1.11]).
Figure 1. Plasma concentration-time profiles for vildagliptin following administration of a 100 mg oral dose alone or in combination with a single 25 mg dose of warfarin in healthy subjects. Symbols denote plasma concentrations of vildagliptin following administration alone (filled circles) or in combination with a single dose of warfarin (open triangles). Data are presented as mean +- SEM (standard error of the mean)
Table 1. Pharmacokinetic parameters of vildagliptin following oral administration of vildagliptin lOOmg alone or in combination with warfarin 25 mg in healthy subjects
Figure 2. Plasma concentration-time profiles for (A) R-warfarin and (B) S-warfarin following administration of a single 25 mg oral dose of warfarin alone or in combination with vildagliptin lOOmgin healthy subjects. Symbols denote plasma concentrations of R- warfarin or S-warfarin following administration of warfarin alone (filled circles) or in combination with vildagliptin (open triangles). Data are presented as mean +- SEM (standard error of the mean)
Pharmacokinetics of H- and S-warfarin
Co-administration of vildagliptin lOOmg with a single 25 mg oral dose of warfarin had no major effect on the plasma concentration- time profile or pharmacokinetic parameters of either R-warfarin or S- warfarin (Figure 2, Table 2). Ratios of geometric mean values were near unity with the 90% CIs being contained within the bioequivalence range of 0.80-1.25 for R-warfarin C^sub max^ (geometric mean ratio 1.02 [90% CI 0.95, 1.11]) and AUC^sub 0_^. (mean ratio 1.00 [90% CI 0.95, 1.04]), and for S-warfarin C^sub max^ (mean ratio 1.02 [90% CI 0.94, 1.1O]) and AUC^sub 0_^ (mean ratio 0.97 [90% CI 0.93, 1.01]).
Pharmacodynamics of warfarin
Mean PT values (raw data and international normalized ratios [INR]) over 168 hours following administration of warfarin were essentially identical when warfarin was administered alone or in combination with vildagliptin (Figure 3). Maximum PT and INR values and areas under the PT-time and INR-time curves were not altered by co-administration with vildagliptin (Table 3); ratios of geometric means were near unity with 90% nce range of 0.80-1.25 for absolute PT or INR values and for changes from predose values (Table 4). Safety and tolerability
Administration of vildagliptin and warfarin alone or in combination was well tolerated. The only adverse event reported during the study was a mild upper respiratory tract infection reported by one subject 12 days after receiving treatment with warfarin and placebo, which was judged not to be related to study medication. This subject did not discontinue the study due to the adverse event but later withdrew consent.
Table 2. Pharmacokinetic parameters of R- and S-warfarin following oral administration of a single dose of warfarin 25 mg alone or in cpmbination with vildaglipin 100 mg once daily in healthy subjects
Figure 3. (A) Mean prothrombin time (PT) and (B) international normalized ratio (INR) following administration of a single 25 mg oral dose ofwarfann alone or in combination with vildagliptin 100 mg in healthy subjects. Symbols denote PT or INR following administration of warfarin alone (filled circles) or in combination with vildagliptin (open triangles). Data are presented as mean +- SEM (standard error of the mean)
There were no clinically significant changes in blood or urine chemistry, vital signs or ECG findings during the course of the study. There were multiple instances of prolonged PT (range 9-13 seconds) or increased INR (range 2-3.5), which would be anticipated following warfarin administration, but no other clinically relevant changes in hematology parameters were observed.
The vitamin K antagonist warfarin has been used for several decades for long-term prevention of thrombosis and thromboembolism. Because warfarin has a narrow therapeutic index, pharmacokinetic or pharmacodynamic interactions with warfarin can have potentially serious consequences14’18. The aim of the present study was to assess the effects of co-administration of warfarin with the potent and selective DPP-4 inhibitor vildagliptin, a novel antihyperglycemic agent, on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. The results showed that co-administration of vildagliptin with warfarin was well tolerated and had no effect on the single-dose pharmacokinetics of either the R- or S-enantiomers of warfarin, or on the anticoagulant effects of warfarin in healthy subjects.
Co-administration of oral vildagliptin lOOmg once daily with a single 25 mg oral dose of warfarin had no effect on the pharmacokinetics of either drug. The ratio of geometric means and associated 90% CIs for the AUC^sub 0_[infinity]^ and C^sub max^ of vildagliptin, R-warfarin and S-warfarin were all contained entirely within the equivalence range 0.801.25. Most pharmacokinetic interactions with warfarin occur as a result of either inhibition (e.g., by miconazole)19 or induction (e.g., by phenytoin)20 of CYP2C9-mediated metabolism of S-warfarin, the more active of the two enantiomers. The lack of effect of vildagliptin on the pharmacokinetics of warfarin is consistent with the fact that vildagliptin does not inhibit or induce the activity of CYP450 isoenzymes in vitro, and exhibits negligible metabolism by CYP450 in vivo (Novartis, data on file). Warfarin is highly protein bound (> 99%). Several drugs such as clofibrate, ibuprofen and cotrimoxazole displace warfarin from plasma proteins18, but the importance of protein binding displacement in drug-drug interactions is controversial14. Effects of vildagliptin on the protein binding of other drugs are unlikely as plasma protein binding of vildagliptin is very low (9.3%).
Table 3. Pharmaeodynamic parameters following oral administration of a single dose of warfarin 25mg alone or in combination with vilaagliptin lOOmg once daily in healthy subjects
Table 4. Ratio of geometric means for pharmacodynamic parameters following oral administration of a single dose of warfarin 25 mg alone or in combination with irildagliptin 100 mg once daily in healthy subjects
Co-administration of multiple doses of vildagliptin with warfarin in the present study had no effect on PT or INR (ratios of geometric means for peak PT or INR values and areas under the PT-time or INR- time curves were all entirely contained within the equivalence range 0.80-1.25). Moreover, the 90% CIs for the area under the PT-time curve were 0.97-1.01, and therefore within the more stringent 0.95- 1.05 equivalence range proposed by Schall et al.21 to take account of the narrow therapeutic index of warfarin. These results indicate that vildagliptin has no effect on the pharmacodynamics of a single dose of warfarin.
A limitation of the present study could be that the pharmacokinetics and pharmacodynamics of warfarin were assessed following administration of only a single dose. The terminal elimination half-lives of R-warfarin and S-warfarin are 35-58 hours and 24-33 hours, respectively, and so the anticoagulant effect of warfarin is likely to be more pronounced following multiple dose administration10. However, unlike the dosing regimen typically used in clinical practice (a loading dose of 5-lOmg warfarin for the first 1 or 2 days and then titration of subsequent doses based on the INR response7), a single 25 mg or 30 mg oral dose of warfarin has been used by many investigators to study the pharmacokinetic and pharmacodynamic interaction with warfarin15’17,22. This provides peak plasma levels and anticoagulant effects of warfarin similar to those observed at steady-state in a clinical dosing regimen, such that the potential for pharmacokinetic and pharmacodynamic interaction can be assessed in healthy volunteers without compromising safety. Consistent with the results of previous studies that have employed a single 25mg oral dose of warfarin15’22, warfarin administration in the present study resulted in an increase in INR, reaching a peak of approximately 2.0 at around 36-48 hours post-dose. Other studies that have shown no drug-drug interaction with single-dose warfarin15’17’22 have also confirmed the lack of drug-drug interaction following chronic administration in clinical practice.
Vildagliptin treatment was well tolerated when administered alone or in combination with a single dose of warfarin in healthy subjects in the present study. Only one adverse event (a case of upper respiratory tract infection that was judged to be mild in severity) was reported; this event was transient, resolved spontaneously, and was not judged to be related to study treatment. With the exception of multiple instances of prolonged PT or increased INR, which would be anticipated following administration of warfarin in healthy subjects, no other clinically relevant changes in hematology parameters, or in blood or urine chemistry, vital signs or ECG findings, were observed during the course of the study. The safety and tolerability profile of vildagliptin in healthy subjects in the present study is consistent with the findings of clinical studies in patients with type 2 diabetes. The lOOmg once daily dosage of vildagliptin is the highest anticipated clinical dose of vildagliptin, and has previously been shown to be effective in improving glycEmie control and associated with a rate of adverse events similar to that of placebo in a 12-week dose-finding study3. Phase 3 clinical trials have shown that vildagliptin 50 mg once daily was well tolerated over up to 1 year of treatment2’4.
In summary, the results of the present study show that the orally active, potent and selective DPP-4 inhibitor vildagliptin does not affect the pharmacokinetics of R-warfarin or S-warfarin, or the anticoagulant effect of warfarin. The pharmacokinetics of vildagliptin were also not altered by administration of a single dose of warfarin. Co-administration of multiple doses of vildagliptin with a single oral dose of warfarin was well tolerated. These results suggest that no dosage adjustment of either vildagliptin or warfarin should be required when these drugs are co- prescribed.
Declaration of interest: This study was supported by Novartis Pharmaceuticals. With the exception of Mitchell Rosenberg, all authors are employees of Novartis Pharmaceuticals Corporation and are eligible for Novartis stock and stock options.
* The results of this study were presented in abstract form at the 35th meeting of the American College of Clinical Pharmacology, Cambridge, MA, USA, September 17-19, 2006
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Paper CMRO-3895_3, Accepted for publication: 20 March 2007
Published Online: 13 April 2007
Yan-Ling Hea, Ron Sabob, Gilles-Jacques Riviere0, Gangadhar Sunkarab, Selene Leonb, Monica LiguerosSaylanb, Mitchell Rosenbergd, William P. Dolea and Dan Howard”
“Exploratory Development, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
6 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
0 Novartis Pharma S.A., Rueil-Malmaison, France
“Parkway Research Center Inc., North Miami Beach, FL, USA
Address for correspondence: Dr Yan-Ling He, Exploratory Development-DMPK, Novartis Institutes for Biomedical Research, 400 Technology Square, Building 605, Cambridge, MA 02139-3584, USA. Tel.: +1-617-871-3065; Fax: +1-617-871-3331; email: [email protected]
Copyright Librapharm May 2007
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