Christopher Banfield

Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans

&NA; The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration‐dependent hyperthermia. Similar to what was observed in rats, dogs, and monkeys, hyperthermia was attenuated after repeated dosing of AMG 517 (at the highest dose tested) in humans during a second Phase I trial. However, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long‐lasting hyperthermia with maximal body temperature surpassing 40 °C, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals. Mechanisms of AMG 517‐induced hyperthermia were then studied in rats. AMG 517 caused hyperthermia by inducing tail skin vasoconstriction and increasing thermogenesis, which suggests that TRPV1 regulates vasomotor tone and metabolic heat production. In conclusion, these results demonstrate that: (a) TRPV1‐selective antagonists like AMG 517 cannot be developed for systemic use as stand alone agents for treatment of pain and other diseases, (b) individual susceptibility influences magnitude of hyperthermia observed after TRPV1 blockade, and (c) TRPV1 plays a pivotal role as a molecular regulator for body temperature in humans.

A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee

IntroductionAMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee.MethodsIn Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score.ResultsIn Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively).ConclusionsThe safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed.Trial RegistrationThis study is registered with ClinicalTrials.gov with the identifier NCT00110942.

Blockade of interferon-γ normalizes interferon-regulated gene expression and serum CXCL10 levels in patients with systemic lupus erythematosus.

To assess the safety and immunologic impact of inhibiting interferon‐γ (IFNγ) with AMG 811, a human IgG1 monoclonal antibody against IFNγ, in patients with systemic lupus erythematosus (SLE).

Model‐Based Drug Development Survey Finds Pharmacometrics Impacting Decision Making in the Pharmaceutical Industry

During the past decade, the pharmaceutical industry has seen the increasing application of pharmacometrics approaches in drug development. However, the full potential of incorporating model‐based approaches in drug development and its impact on decision making has not been fully realized to date. In 2009, a survey on model‐based drug development (MBDD) was conducted (1) to further understand the current state of MBDD in the pharmaceutical industry and (2) to identify opportunities to realize the full potential of MBDD. Ten large and mid‐sized pharmaceutical companies provided responses to this survey. The results indicate that MBDD is achieving broad application in early and late development and is positively affecting both internal and regulatory decisions. Senior leadership (vice president and higher) within the companies indicated widely accepted utility for dose selection and gaining acceptance for study design and regulatory interactions but limited acceptance in discovery and commercial/pipeline decisions. Mounting appreciation for the impact of MBDD on internal and regulatory decision‐making bodes well for the future of the pharmacometric discipline and the growth of opportunities to realize the full potential of MBDD.

Blockade of interferon‐gamma (IFN‐γ) normalizes IFN regulated gene expression and serum CXCL10 (IP‐10) in subjects with systemic lupus erythematosus (SLE)

To assess the safety and immunologic impact of inhibiting interferon‐γ (IFNγ) with AMG 811, a human IgG1 monoclonal antibody against IFNγ, in patients with systemic lupus erythematosus (SLE).

Model-Based Drug Development: Strengths, Weaknesses, Opportunities, and Threats for Broad Application of Pharmacometrics in Drug Development

Systematic implementation of model‐based drug development (MBDD) to drug discovery and development has the potential to significantly increase the rate of medical breakthroughs and make available new and better treatments to patients. An analysis of the strengths, weaknesses, opportunities, and threats (ie, SWOT) was conducted through focus group discussions that included 24 members representing 8 pharmaceutical companies to systematically assess the challenges to implementing MBDD into the drug development decision‐making process. The application of the SWOT analysis to the successful implementation of MBDD yielded 19 strengths, 27 weaknesses, 34 opportunities, and 22 threats, which support the following conclusions. The shift from empirical drug development to MBDD requires a question‐based mentality; early, proactive planning; dynamic access to multisource data; quantitative knowledge integration; multidisciplinary collaboration; effective communication and leadership skills; and innovative, impactful application of pharmacometrics focused on enhancing quantitative decision making. The ultimate goal of MBDD is to streamline discovery and development of innovative medicines to benefit patients.

Modeling the Exposure‐Response Relationship of Etanercept in the Treatment of Patients With Chronic Moderate to Severe Plaque Psoriasis

Modeling exposure‐response relationships adds significant value to comprehending and interpreting both efficacy and safety data. An exposure‐response model was developed using generalized nonlinear mixed‐effects methodologies to correlate etanercept exposure with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI75). Three randomized trials of psoriasis patients were pooled for analysis. Three empirical exposure measures—cumulative dose, predicted cumulative area under the curve, and predicted trough concentration—were evaluated for their predictive capabilities. The predicted cumulative area under the curve model demonstrated the best ability via simulation to reproduce the data and was used to assess the following covariates: age, baseline psoriasis area and severity index, duration of psoriasis disease, prior systemic or phototherapy, race, sex, and weight. The final model was composed by scrutinizing the confidence intervals of a nonparametric bootstrap and included race and sex effects on baseline logit, baseline psoriasis area and severity index and prior systemic or phototherapy effects on maximum drug effect, a weight effect on apparent potency, and an age effect on the rate of drug effect. The model identified covariates predictive of data trends and adequately characterized by simulation the PASI75 over the entire clinical trial design space. In combination with a statistical subgroup analysis, the exposure‐response model indicated that dose adjustment was not necessary for etanercept in any patient subpopulation with moderate to severe plaque psoriasis.

Predicting the Drug Interaction Potential of AMG 853, a Dual Antagonist of the D-Prostanoid and Chemoattractant Receptor-Homologous Molecule Expressed on T Helper 2 Cells Receptors

2-(4-(4-(tert-Butylcarbamoyl)-2-(2-chloro-4-cyclopropylphenylsulfonamido)phenoxy)-5-chloro-2-fluorophenyl)acetic acid (AMG 853) is an orally bioavailable and potent dual antagonist of the D-prostanoid and chemoattractant receptor-homologous molecule expressed on T helper 2 cells receptors. The drug interaction potential of AMG 853, both as a victim and a perpetrator, was investigated using in vitro, in silico, and in vivo methodologies. Experiments in human liver microsomes (HLM) and recombinant enzymes identified CYP2C8, CYP2J2, and CYP3A as well as multiple UDP-glucuronosyltransferase isoforms as being responsible for the metabolic clearance of AMG 853. With use of HLM and selective probe substrates, both AMG 853 and its acyl glucuronide metabolite (M1) were shown to be inhibitors of CYP2C8. AMG 853 and M1 did not inhibit any of the other cytochrome P450 isoforms tested, and AMG 853 exhibited minimal enzyme induction properties in human hepatocytes cultures. In light of the in vitro findings, modeling and simulation approaches were used to examine the potential for ketoconazole (a CYP3A inhibitor) to inhibit the metabolism of AMG 853 as well as for AMG 853 to inhibit the metabolism of paclitaxel, rosiglitazone, and montelukast, commonly used substrates of CYP2C8. A weak and clinically insignificant drug interaction (area under the drug concentration-time curve (AUC)i/AUC <2) was predicted between ketoconazole and AMG 853. No drug interactions were predicted for AMG 853 and paclitaxel, rosiglitazone, or montelukast. Finally, administration of AMG 853 to healthy human subjects in clinical trials in the presence or absence of ketoconazole confirmed that AMG 853 is unlikely to be involved in clinically significant drug interactions.