Rajesh Krishna

Publications (29)124.58 Total impact

• Article: Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.

  Rajesh Krishna, Daria Stypinski, Melissa Ali, Amit Garg, Josee Cote, Andrea Maes, Bruce Degroot, Yang Liu, Susie Li, Sandra M Connolly, John A Wagner, S Aubrey Stoch
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  ABSTRACT: • Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY: ADDS • This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib. Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg Coumadin(TM) ) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day -14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC((0-∞)) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(-) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin C(max) were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(-) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC((0-168 h)) was 0.93 (0.89, 0.96). The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib.
  British Journal of Clinical Pharmacology 01/2012; 74(1):116-24. · 2.96 Impact Factor
• Article: Lack of an effect of anacetrapib on the pharmacokinetics of digoxin in healthy subjects.

  Rajesh Krishna, Daria Stypinski, Melissa Ali, Amit Garg, Isaias Noel Gendrano, Andrea Maes, Bruce DeGroot, Yang Liu, Susie Li, Sandra M Connolly, John A Wagner, S Aubrey Stoch
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  ABSTRACT: Anacetrapib is currently being developed for the oral treatment of dyslipidemia. A clinical study was conducted in healthy subjects to assess the potential for an interaction with orally administered digoxin. Anacetrapib was generally well tolerated when co-administered with digoxin in the healthy subjects in this study. The geometric mean ratios (GMR) for (digoxin + anacetrapib/digoxin alone) and 90% confidence intervals (CIs) for digoxin AUC(0-last) and AUC(0-∞) were 1.05 (0.96, 1.15) and 1.07 (0.98, 1.17), respectively, both being contained in the accepted interval of bioequivalence (0.80, 1.25), the primary hypothesis of the study. The GMR (digoxin + anacetrapib /digoxin alone) and 90% CIs for digoxin C(max) were 1.23 (1.14, 1.32). Median T(max) and mean apparent terminal t(½) of digoxin were comparable between the two treatments. The single-dose pharmacokinetics of orally administered digoxin were not meaningfully affected by multiple-dose administration of anacetrapib, indicating that anacetrapib does not meaningfully inhibit P-glycoprotein. Thus, no dosage adjustment for digoxin is necessary when co-administered with anacetrapib.
  Biopharmaceutics & Drug Disposition 12/2011; 32(9):525-9. · 2.07 Impact Factor
• Article: Model-based development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor.

  Rajesh Krishna, Arthur J Bergman, Michele Green, Marissa F Dockendorf, John A Wagner, Kevin Dykstra
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  ABSTRACT: A model-based strategy was used to inform the early clinical development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor under development for the treatment of hyperlipidemia. The objectives of this model-based approach were to enable bridging variable pharmacokinetic effects, differences among formulations used in development, and to identify an appropriate dose for the phase III confirmatory program. Nonlinear mixed effects PK/PD models were initially developed based on data obtained from multiple phase I studies and later were updated with data from a phase IIb study. The population pharmacokinetic model described differences between the liquid-filled capsule used in phase I and phase IIb and the hot-melt extruded (HME) tablet formulation introduced in phase III, allowing for bridging of the two formulations, and quantified the complex relationship of apparent anacetrapib bioavailability with subject meal intake. Proportional E(max) models quantified the relationships between anacetrapib trough concentration and lipoprotein effects (LDL-C and HDL-C), with covariate effects of study population (normal volunteers vs. patients), and co-administration with HMG-CoA reductase inhibitor ("statin"). The interaction between anacetrapib and atorvastatin suggested pharmacological independence, i.e., that when given together, each agent exerts the same proportional lipid effect observed from monotherapy. Clinical trial simulation was used to examine the robustness of the effects to random dietary indiscretion, and found that the results were robust as long as patients generally adhered to a low-fat diet. These results allowed the selection of the 100 mg dose with the HME formulation for phase III development even though this dose and formulation were not specifically studied in a phase IIb trial.
  The AAPS Journal 02/2011; 13(2):179-90. · 5.09 Impact Factor
• Article: Applications of 'decisionable' biomarkers in cardiovascular drug development.

  Rajesh Krishna, John A Wagner
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  ABSTRACT: Biomarkers are now increasingly employed in drug development for decision-making. New targets and candidate drugs should not only have drug-like properties (i.e., be 'drugable'), but the supporting biomarker platform should be 'decisionable'. For example, biomarkers for target engagement have supported the biologic plausibility for novel mechanisms and have aided in accelerated proof of concept. In many other circumstances, biomarkers have aided in the elucidation of mechanisms of action and disease progression. In this article, decisonable biomarker principles that aid in decision-making within the realm of early discovery through to clinical proof of concept are discussed. Case studies of applications of both target engagement and disease-related biomarkers are illustrated in the field of cardiovascular drug discovery and translational development. We propose that biomarkers, if prospectively implemented in an early development program, have the potential to accelerate drug development, facilitate the design of informative trials and dose selection for accelerated development, and establish an overall increase in probability of developmental success and efficiency.
  Biomarkers in Medicine 12/2010; 4(6):815-27. · 0.86 Impact Factor
• Article: Effect of diltiazem, a moderate CYP3A inhibitor, on the pharmacokinetics of anacetrapib, a potent cholesteryl ester transfer protein inhibitor, in healthy subjects.

  Amit Garg, Andrea Maes, Christy Corr, Bo Jin, Tarun Wadhwa, Nikhil Handa, Kristien Van Dyck, Inge De Lepeleire, Jinesh Shah, John A Wagner, Rajesh Krishna
  The Journal of Clinical Pharmacology 04/2010; 51(3):436-9. · 2.91 Impact Factor
• Article: Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans.

  Sanjeev Kumar, Eugene Y Tan, Georgy Hartmann, Zachary Biddle, Arthur J Bergman, James Dru, Jonathan Z Ho, Allen N Jones, Steve J Staskiewicz, Matthew P Braun, Bindhu Karanam, Dennis C Dean, Isaias Noel Gendrano, Mark W Graves, John A Wagner, Rajesh Krishna
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  ABSTRACT: Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 microCi of [(14)C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites. The majority of the administered radioactivity (87%) was eliminated by fecal excretion, with negligible amounts present in urine (0.1%). The peak level of radioactivity in plasma (approximately 2 microM equivalents of [(14)C]anacetrapib) was achieved approximately 4 h postdose. The parent compound was the major radioactive component (79-94% of total radioactivity) in both plasma and feces. Three oxidative metabolites, M1, M2, and M3, were detected in plasma and feces and were identified as the O-demethylated species (M1) and two secondary hydroxylated derivatives of M1 (M2 and M3). Each metabolite was detected at low levels, representing <or=14% of the radioactivity in plasma or fecal samples. In vitro data indicated that anacetrapib is metabolized mainly by CYP3A4 to form M1, M2, and M3. Overall, these data, along with those from other preclinical and clinical studies, indicate that anacetrapib probably exhibits a low-to-moderate degree of oral absorption in humans and the absorbed fraction of the dose is eliminated largely via CYP3A4-catalyzed oxidative metabolism, followed by excretion of metabolites by the biliary-fecal route.
  Drug metabolism and disposition: the biological fate of chemicals 12/2009; 38(3):474-83. · 3.74 Impact Factor
• Article: Model-based evaluation of QTc interval risk: an increasing emphasis on early decision making.

  Rajesh Krishna
  The Journal of Clinical Pharmacology 10/2009; 49(9):1010-1. · 2.91 Impact Factor
• Article: Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

  Rajesh Krishna, Amit Garg, Deborah Panebianco, Josee Cote, Arthur J Bergman, Pascale Van Hoydonck, Tine Laethem, Kristien Van Dyck, Jingjing Chen, Cynthia Chavez-Eng, [......], Ryan Lutz, Deborah Hilliard, Karen Snyder, Bo Jin, Luc Van Bortel, Kenneth C Lasseter, Nidal Al-Huniti, Kevin Dykstra, Keith Gottesdiener, John A Wagner
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  ABSTRACT: Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib. Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated. Anacetrapib was rapidly absorbed, with peak concentrations occurring at approximately 4 h post-dose and an apparent terminal half-life ranging from approximately 9 to 62 h in the fasted state and from approximately 42 to approximately 83 h in the fed state. Plasma AUC and C(max) appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of approximately 90% inhibition at t(max) and approximately 58% inhibition at 24 h post-dose. An E(max) model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC(50) of approximately 22 nm. Food increased exposure to anacetrapib; up to approximately two-three-fold with a low-fat meal and by up to approximately six-eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure. Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.
  British Journal of Clinical Pharmacology 10/2009; 68(4):535-45. · 2.96 Impact Factor
• Article: Evaluation of agile designs in first-in-human (FIH) trials--a simulation study.

  Itay Perlstein, James A Bolognese, Rajesh Krishna, John A Wagner
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  ABSTRACT: The aim of the investigation was to evaluate alternatives to standard first-in-human (FIH) designs in order to optimize the information gained from such studies by employing novel agile trial designs. Agile designs combine adaptive and flexible elements to enable optimized use of prior information either before and/or during conduct of the study to seamlessly update the study design. A comparison of the traditional 6 + 2 (active + placebo) subjects per cohort design with alternative, reduced sample size, agile designs was performed by using discrete event simulation. Agile designs were evaluated for specific adverse event models and rates as well as dose-proportional, saturated, and steep-accumulation pharmacokinetic profiles. Alternative, reduced sample size (hereafter referred to as agile) designs are proposed for cases where prior knowledge about pharmacokinetics and/or adverse event relationships are available or appropriately assumed. Additionally, preferred alternatives are proposed for a general case when prior knowledge is limited or unavailable. Within the tested conditions and stated assumptions, some agile designs were found to be as efficient as traditional designs. Thus, simulations demonstrated that the agile design is a robust and feasible approach to FIH clinical trials, with no meaningful loss of relevant information, as it relates to PK and AE assumptions. In some circumstances, applying agile designs may decrease the duration and resources required for Phase I studies, increasing the efficiency of early clinical development. We highlight the value and importance of useful prior information when specifying key assumptions related to safety, tolerability, and PK.
  The AAPS Journal 09/2009; 11(4):653-63. · 5.09 Impact Factor
• Article: A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular repolarization in healthy subjects.

  Daniel M Bloomfield, Rajesh Krishna, David Hreniuk, Lisa Hickey, Kalyan Ghosh, Arthur J Bergman, Jutta Miller, Maria J Gutierrez, Randall Stoltz, Keith M Gottesdiener, Gary A Herman, John A Wagner
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  ABSTRACT: A randomized, double-blind, placebo-controlled, 4-period crossover study was performed with a single oral dose of sitagliptin (100 mg, 800 mg), moxifloxacin (400 mg), and placebo in order to provide a rigorous assessment of the effect of sitagliptin on ventricular repolarization based on the ICH E14 guidance. The clinical dose of sitagliptin 100 mg was not associated with an increase in QTc interval, corrected using the Fridericia correction (QTcf), at any time point. The supratherapeutic 800-mg dose of sitagliptin was generally well tolerated and was associated with minimal, clinically insignificant prolongation of the QTcf interval at concentrations approximately 11-fold higher than maximal concentrations following the 100-mg clinical dose. The PK/QTc model demonstrated a shallow relationship between the plasma concentration of sitagliptin and the placebo-subtracted QTcf change from baseline, with a 0.59-millisecond increase in QTc for every 1000-nM increment in sitagliptin plasma concentration. The sensitivity of the assay to detect modest increases in QTc interval was established with the active control moxifloxacin. In conclusion, at clinically relevant concentrations, sitagliptin is not associated with clinically meaningful QTcf prolongation.
  The Journal of Clinical Pharmacology 09/2009; 49(8):937-46. · 2.91 Impact Factor
• Article: Assessment of a pharmacokinetic and pharmacodynamic interaction between simvastatin and anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects.

  Rajesh Krishna, Amit Garg, Bo Jin, Sara Sadeghi Keshavarz, Frederick A Bieberdorf, Jeffrey Chodakewitz, John A Wagner
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  ABSTRACT: Anacetrapib is an orally active, potent inhibitor of cholesteryl ester transfer protein (CETP), which is in development for the treatment of dyslipidaemia. Because of the likely use of anacetrapib with hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, we aimed to evaluate the potential for a pharmacokinetic interaction with simvastatin. A randomized, two-period, two-treatment, balanced, open-label, crossover study in 12 healthy subjects was performed. Subjects received simvastatin 40 mg alone or anacetrapib 150 mg co-administered with simvastatin 40 mg, once daily. Both treatments were administered following a low-fat breakfast for 14 days, separated by a wash-out period of at least 14 days. Safety and tolerability, simvastatin and simvastatin acid concentrations, and lipoproteins, were assessed. Both treatments were well tolerated. The pharmacokinetics of simvastatin and simvastatin acid were similar with and without anacetrapib administration {AUC(0-24 h) geometric mean ratio [90% confidence interval (CI)] for simvastatin acid and simvastatin were 1.36 [1.17, 1.57] and 1.30 [1.14, 1.47], respectively} based on the prespecified comparability bounds of (0.50, 2.00). Treatment with simvastatin alone led to a mean (95% CI) % reduction from baseline in low-density lipoprotein-cholesterol (LDL-C) of -36% (-27, -46) compared with a reduction of -54% (-44, -63) for anacetrapib co-administered with simvastatin. There appears to be no clinically meaningful effect of anacetrapib on the pharmacokinetic parameters of simvastatin. When co-administered with simvastatin, anacetrapib appeared to exhibit incremental LDL-C-lowering efficacy, due to CETP inhibition. Co-administration of anacetrapib and simvastatin was well tolerated.
  British Journal of Clinical Pharmacology 06/2009; 67(5):520-6. · 2.96 Impact Factor
• Article: The use of clinical utility assessments in early clinical development.

  Anis A Khan, Itay Perlstein, Rajesh Krishna
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  ABSTRACT: A quickly realizable benefit of model-based drug development is in reducing uncertainty in risk/benefit, comprising individually of safety and effectiveness, two key attributes of a product evaluated for regulatory approval, marketing, and use. In this review, we investigate gaps and opportunities in using fundamental decision analytic principles in drug development and present a quantitative clinical pharmacology framework for the application of such aids for early clinical development decision making. We anticipate that implementation of such emerging tools will enable sufficient scientific understanding of the two attributes to facilitate the early termination of compounds with less than desirable risk/benefit profiles and continuance of compounds with acceptable risk/benefit profiles.
  The AAPS Journal 02/2009; 11(1):33-8. · 5.09 Impact Factor
• Article: Assessment of the CYP3A-mediated drug interaction potential of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy volunteers.

  Rajesh Krishna, Arthur J Bergman, Bo Jin, Amit Garg, Brad Roadcap, Rita Chiou, James Dru, Josee Cote, Tine Laethem, Regina W Wang, Varsha Didolkar, Eva Vets, Keith Gottesdiener, John A Wagner
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  ABSTRACT: In this study, midazolam was used as a probe-sensitive CYP3A substrate to investigate the effect of anacetrapib on CYP3A activity, and ketoconazole was used as a probe-inhibitor to investigate the effect of potent CYP3A inhibition on the pharmacokinetics of anacetrapib, a novel cholesteryl ester transfer protein inhibitor in development for the treatment of dyslipidemia. Two partially blinded, randomized, 2-period, fixed-sequence studies were performed. Safety, tolerability, and midazolam and anacetrapib plasma concentrations were assessed. All treatments were generally well tolerated. The geometric mean ratios (90% confidence interval) of midazolam with anacetrapib/midazolam alone for AUC0-infinity and Cmax were 1.04 (0.94, 1.14) and 1.15 (0.97, 1.37), respectively. Exposure to anacetrapib was increased by ketoconazole--specifically, the geometric mean ratios (90% confidence interval) of anacetrapib with ketoconazole/anacetrapib alone for AUC0-infinity and Cmax were 4.58 (3.68, 5.71) and 2.37 (2.02, 2.78), respectively. The study showed that anacetrapib does not inhibit or induce CYP3A activity. Furthermore, anacetrapib appears to be a moderately sensitive substrate of CYP3A.
  The Journal of Clinical Pharmacology 12/2008; 49(1):80-7. · 2.91 Impact Factor
• Source

  Available from: PubMed Central

  Article: Accelerating drug development using biomarkers: a case study with sitagliptin, a novel DPP4 inhibitor for type 2 diabetes.

  Rajesh Krishna, Gary Herman, John A Wagner
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  ABSTRACT: The leveraged use of biomarkers presents an opportunity in understanding target engagement and disease impact while accelerating drug development. For effective integration in drug development, it is essential for biomarkers to aid in the elucidation of mechanisms of action and disease progression. The recent years have witnessed significant progress in biomarker selection, validation, and qualification, while enabling surrogate and clinical endpoint qualification and application. Biomarkers play a central role in target validation for novel mechanisms. They also play a central role in the learning/confirming paradigm, particularly when utilized in concert with pharmacokinetic/pharmacodynamic modeling. Clearly, these attributes make biomarker integration attractive for scientific and regulatory applications to new drug development. In this review, applications of proximal, or target engagement, and distal, or disease-related, biomarkers are highlighted using the example of the recent development of sitagliptin for type 2 diabetes, wherein elucidation of target engagement and disease-related biomarkers significantly accelerated sitagliptin drug development. Importantly, use of biomarkers as tools facilitated design of clinical efficacy trials while streamlining dose focus and optimization, the net impact of which reduced overall cycle time to filing as compared to the industry average.
  The AAPS Journal 07/2008; 10(2):401-9. · 5.09 Impact Factor
• Article: Lack of erectogenic activity of a novel selective melanocortin-4 receptor agonist in a clinical experimental model.

  Rajesh Krishna, Peggy Wong, Catherine Stevens, Inge De Lepeleire, Kristien Van Dyck, Raymond C Rosen, Isaias Noel Gendrano, Mathieu Peeters, John A Wagner, Gary A Herman
  The Journal of Clinical Pharmacology 07/2008; 48(10):1237-41. · 2.91 Impact Factor
• Article: Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies.

  Rajesh Krishna, Matt S Anderson, Arthur J Bergman, Bo Jin, Marissa Fallon, Josee Cote, Kim Rosko, Cynthia Chavez-Eng, Ryan Lutz, Daniel M Bloomfield, Maria Gutierrez, James Doherty, Fredrick Bieberdorf, Jeffrey Chodakewitz, Keith M Gottesdiener, John A Wagner
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  ABSTRACT: The inhibition of cholesteryl ester transfer protein (CETP) is considered a potential new mechanism for treatment of dyslipidaemia. Anacetrapib (MK-0859) is a CETP inhibitor currently under development. We aimed to assess anacetrapib's effects as monotherapy on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) and on 24-h ambulatory blood pressure. We did two double-blind, randomised, placebo-controlled phase I studies. In the first study, 50 patients with dyslipidaemia (LDL-C 100-190 mg/dL; 40 active, 10 placebo) aged 18-75 years received anacetrapib doses of 0, 10, 40, 150, or 300 mg orally once a day with a meal for 28 days. Standard lipid and lipoprotein monitoring, safety monitoring, and anacetrapib concentrations for pharmacokinetics were done. In the second study, 22 healthy participants aged 45-75 years received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period, in a randomised sequence, with at least a 14-day washout between the treatment periods. Continuous 24-h ambulatory blood pressure monitoring was done on day -1 and day 10 of each treatment period in this study. The primary or secondary endpoints of safety and tolerability were assessed in both studies by monitoring clinical adverse experiences, physical examinations, vital signs, 12-lead electrocardiogram, and laboratory safety. Analysis was per protocol. These trials are registered with ClinicalTrials.gov, number NCT00565292 and NCT00565006. In the dyslipidaemia study, one patient withdrew consent and one was excluded from the data analysis for HDL-C and LDL-C because complete pre-dose measurements were not available. Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129% (mean 51.1 [SD 3.8]-114.9 [7.9] mg/dL) increase in HDL-C and a 38% (138.2 [11.4]-77.6 [7.9] mg/dL) decrease in LDL-C in patients with dyslipidaemia. In the 24-h ambulatory blood pressure study in healthy individuals, least squares difference between anacetrapib and placebo groups on day 10 were 0.60 (90% CI -1.54 to 2.74; p=0.634) mm Hg for systolic blood pressure and 0.47 (90% CI -0.90 to 1.84; p=0.561) mm Hg for diastolic blood pressure. Anacetrapib seems to exhibit HDL-C increases greater than those seen with other investigational drugs in this class and LDL-C lowering effects similar to statins. Despite greater lipid-altering effects relative to other members of this class, anacetrapib seems not to increase blood pressure, suggesting that potent CETP inhibition by itself might not lead to increased blood pressure.
  The Lancet 01/2008; 370(9603):1907-14. · 38.28 Impact Factor
• Article: Dose-proportionality of a final market image sitagliptin formulation, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.

  Arthur Bergman, Goutam C Mistry, Wen-Lin Luo, Q Liu, Julie Stone, Amy Wang, Wei Zeng, Li Chen, Stacy Dilzer, Kenneth Lasseter, Gary A Herman, John A Wagner, Rajesh Krishna
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  ABSTRACT: Sitagliptin is a highly selective orally active dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. Ten healthy subjects received single oral doses of 25, 50, 100, 200 and 400 mg final market image tablets in five separate treatment periods in randomized fashion to assess dose proportionality. Blood (up to 72 h post-dose) and urine (up to 24 h post-dose) samples for sitagliptin pharmacokinetic analysis were collected at pre-specified times following administration of sitagliptin. Dose-proportionality of AUC(0-infinity), C(max) and C(24 h) was assessed using a power-law model. The results of this study indicate that plasma AUC(0-infinity) increased in a dose-proportional manner over the 25-400 mg dose range. Over the same dose range, plasma C(max) increased in a greater than dose-proportional manner and C(24 h) increased in a modestly less than dose proportional manner. No clinically meaningful differences in T(max) or apparent t(1/2) were noted across the dose range. Differences in the percentage of the sitagliptin dose excreted unchanged in urine (72.5% pooled across doses) and renal clearance (344 ml/min pooled across doses) were not statistically significant. Sitagliptin was generally well tolerated at all the doses evaluated.
  Biopharmaceutics & Drug Disposition 10/2007; 28(6):307-13. · 2.07 Impact Factor
• Article: Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.

  Arthur Bergman, David Ebel, Fang Liu, Julie Stone, Amy Wang, Wei Zeng, Li Chen, Stacy Dilzer, Kenneth Lasseter, Gary Herman, John Wagner, Rajesh Krishna
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  ABSTRACT: The purpose of this study was to determine the absolute bioavailability of sitagliptin, an orally active, potent and highly selective dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. The effect of a high fat meal on sitagliptin pharmacokinetics was also assessed. The study was performed in two parts. Intravenous doses (2 h infusion) of 25, 50 and 100 mg were administered double-blind to 10 (8 active, 2 placebo) subjects in a fixed-sequence manner in Part I. In Part II, 12 subjects were randomized to each of three open-label treatments: an intravenous 100 mg dose; a single oral 100 mg final market image tablet administered following a high fat meal and a single oral 100 mg final market image tablet administered fasted. Following each dose, plasma and urine were collected at pre-specified times for evaluation of sitagliptin pharmacokinetics. All doses were generally well tolerated in both parts of the study. Following rising intravenous doses of sitagliptin, AUC(0-infinity) increased dose-proportionally, indicating that plasma clearance is independent of dose over the dose range evaluated. Renal clearance of unchanged sitagliptin accounted for approximately 70% of the total plasma clearance of sitagliptin, indicating that sitagliptin is primarily cleared via renal excretion. Averaged across doses, the mean total plasma clearance was 416 ml/min. The mean absolute bioavailability of sitagliptin was 87% with a 90% CI of (81%, 93%). The AUC(0-infinity) and C(max) geometric mean ratios (fed/fasted) and 90% CIs were 1.03 (0.97, 1.11) and 0.94 (0.86, 1.03), respectively, and were contained within the bounds of (0.80, 1.25). Additionally, the high-fat meal had no significant effect on T(max) or apparent terminal t(1/2). Thus, food does not affect the pharmacokinetics of sitagliptin and therefore can be administered without regard to food.
  Biopharmaceutics & Drug Disposition 10/2007; 28(6):315-22. · 2.07 Impact Factor
• Article: Effective integration of systems biology, biomarkers, biosimulation, and modeling in streamlining drug development.

  Rajesh Krishna, Hans Guenter Schaefer, Ole J Bjerrum
  The Journal of Clinical Pharmacology 07/2007; 47(6):738-43. · 2.91 Impact Factor
• Article: Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults.

  Ira Gantz, Ngozi Erondu, Madhuja Mallick, Bret Musser, Rajesh Krishna, Wesley K Tanaka, Karen Snyder, Cathy Stevens, Mark A Stroh, Haiyuan Zhu, John A Wagner, Douglas J Macneil, Steven B Heymsfield, John M Amatruda
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  ABSTRACT: The gastrointestinal peptide hormone, peptide YY(3-36) (PYY(3-36)), is implicated to be a postprandial satiety factor. The aim of this study is to assess the safety, tolerability, and efficacy of intranasal PYY(3-36) to induce weight loss in obese patients. The study was designed as a randomized, 2-wk, single-blind placebo run-in followed by a 12-wk double-blind, placebo-controlled treatment period. The study was set within a private and institutional practice. A total of 133 obese patients (body mass index, 30-43 kg/m(2); age, 18-65 yr) participated in the study. Placebo or 200- or 600-microg PYY(3-36) was administered as an intranasal spray 20 min before breakfast, lunch, and dinner in conjunction with a hypocaloric diet and exercise. Body weight was the main outcome measure. The number of patients completing 12 wk on the drug was 38 of 43 (88%), 31 of 44 (70%), and 12 of 46 (26%) for placebo, 200 microg three times a day (t.i.d.) and 600 microg t.i.d., respectively. In the 600 microg t.i.d. group, 27 of 46 (59%) patients discontinued due to nausea and vomiting. Among all randomized patients who took at least one drug dose and had a postbaseline measurement, the mean body weight change from baseline was -2.8, -3.7, and -1.4 kg for placebo, 200 and 600 microg, respectively. The least squares mean difference (95% confidence interval) between placebo and 200 microg was -0.9 (-2.6, 0.7) kg (P = 0.251). A difference of 2.11 kg was sought. No meaningful inference can be drawn from the few patients who completed the study on 600 microg. Intranasal PYY(3-36) as administered at these intervention doses and preprandial timing is not efficacious in inducing weight loss in obese patients after 12 wk of treatment.
  Journal of Clinical Endocrinology &amp Metabolism 06/2007; 92(5):1754-7. · 6.50 Impact Factor