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PubMed | Quantitative Solutions Inc., Hoffmann-La Roche and Genentech
Type: Clinical Trial, Phase III | Journal: Cancer chemotherapy and pharmacology | Year: 2016

To characterize the population pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) trastuzumab in early breast cancer (EBC), assess the impact of covariates on trastuzumab PK, and evaluate fixed (nonweight-based) dosing for the SC regimen administrated via handheld syringe.Serum trastuzumab concentrations from 595 patients with HER2-positive EBC in the HannaH study (fixed 600 mg SC trastuzumab or weight-based IV trastuzumab) were analyzed using nonlinear mixed-effects modeling. Multiple logistic regression was used to assess the exposure-response relationships between PK, efficacy [pathologic complete response (pCR)], and safety [grade 3 adverse events (AEs)].Trastuzumab PK was described by a two-compartment model with parallel linear and nonlinear elimination and first-order SC absorption, with a bioavailability of 77 %. Estimated total clearance (CL) values were 0.18-0.22 L/day for steady-state trough/peak concentrations of 75-148 g/mL; the estimate for central volume of distribution was 2.9 L. Body weight and alanine transaminase, while showing significant effects on PK, only explained 8% of the variability in CL. Exposure-response analyses showed no relationship between PK, pCR, and grade 3 AEs for either regimen.A fixed 600 mg SC dose of trastuzumab provides the desired exposure, with steady-state trough concentrations (35-123 g/mL for the 5th-95th percentiles) above the historical target concentration of 20 g/mL for efficacy. Fixed dosing is further supported by lack of an exposure-response relationship between PK, pCR, and grade 3 AEs. No dose adjustment per patient factors is required within the ranges studied.


Daddona P.E.,Zosano Pharma | Matriano J.A.,Zosano Pharma | Mandema J.,Quantitative Solutions Inc. | Maa Y.-F.,Zosano Pharma
Pharmaceutical Research | Year: 2011

Objectives: To evaluate the clinical PK/PD of PTH(1-34) delivered by a novel transdermal drug-coated microneedle patch system (ZP-PTH) for the treatment of osteoporosis. Methods: Phase 1 PK studies evaluated the effect of site of administration, patch wear time and dose in normal volunteers, ages 40-85 yrs. Phase 2 was conducted in post-menopausal women with osteoporosis to determine the patch dose response compared to placebo patch and FORTEO® injection. Results: Phase 1 ZP-PTH patch delivery demonstrated a rapid PTH plasma pulse profile with Tmax 3 times shorter and apparent T 1/2 2 times shorter than FORTEO®. In Phase 2, ZP-PTH 20, 30 and 40 μg doses showed a proportional increase in plasma PTH AUC. Inter-subject and intra-subject AUC variability was similar for all patch doses and comparable to injection. All patch doses produced a significant increase in spine bone mineral density. Unexpectedly, ZP-PTH also produced an early increase in hip bone mineral density, an effect not observed with the injection. Conclusions: These studies suggest that this novel ZP-PTH patch system can deliver a consistent and therapeutically relevant PTH PK profile. Based on encouraging Phase 2 safety and efficacy data, the program is advancing into a pivotal Phase 3 clinical study. © 2010 Springer Science+Business Media, LLC.


Mandema J.W.,Quantitative Solutions Inc. | Boyd R.A.,Pfizer | Dicarlo L.A.,Pfizer | Dicarlo L.A.,Proteus Biomedical, Inc.
Clinical Pharmacology and Therapeutics | Year: 2011

Information on the comparative effectiveness of drugs is crucial for drug development decisions, in addition to being needed by regulators, prescribers, and payers. We have carried out a dose-response meta-analysis of three end points each for efficacy and bleeding for various anticoagulants evaluated for the prevention of venous thromboembolism (VTE) following orthopedic surgery to assess the comparative efficacy and safety of various classes of agents. Data obtained from 89 randomized controlled trials of 23 anticoagulants representing seven drug classes were analyzed. The analysis showed significant differences in the therapeutic index (TI), the ratio of the dose with an acceptable bleeding risk to the dose with a relevant risk reduction for VTE, across the drug classes but not for drugs within a class. The direct inhibitors of FXa, the activated form of factor Xalso known as prothrombinasewere found to have a significantly higher TI than that of any other class of anticoagulants, including enoxaparin, suggesting that this mechanism of action provides the best safety-to-efficacy margin. © 2011 American Society for clinical Pharmacology and Therapeutics.


Cohen A.T.,King's College | Boyd R.A.,Pfizer | Mandema J.W.,Quantitative Solutions Inc. | Dicarlo L.,Proteus Biomedical, Inc. | Pak R.,Pfizer
Journal of Thrombosis and Haemostasis | Year: 2013

Background: PD 0348292 is an oral, selective, direct and reversible factor Xa inhibitor. This was an adaptive dose-ranging study evaluating a 100-fold PD 0348292 dose range in subjects undergoing total knee replacement (TKR). Objective: To assess the efficacy and safety of a dose range of PD 0348292 relative to enoxaparin for the prevention of venous thromboembolism (VTE). Methods: Extensive dose-response modeling and trial simulations were used to select the PD 0348292 dose range for the Phase 2 study. Subjects were randomized to a blinded PD 0348292 dose (0.1 mg qd to 10 mg qd) or open-label enoxaparin (30 mg bid) for 6-14 days after TKR surgery. Efficacy was assessed by mandatory bilateral venography. Results were analyzed using a dose-response modeling approach. Results: Observed VTE frequency ranged from 1.4-37.1% across PD 0348292 doses and was 18.1% for enoxaparin. The PD 0348292 dose-response relationship for VTE was statistically significant (P < 0.0001). The dose of PD 0348292 equivalent to enoxaparin 30 mg bid for VTE prevention was estimated to be 1.16 mg (95% CI = 0.56 mg, 2.41 mg) qd. Total bleeding ranged from 4.9% to 13.8% across PD 0348292 doses and was 6.3% with enoxaparin. The dose-response relationship for total bleeding was not statistically significant (P = 0.2464). Overall, PD 0348292 and enoxaparin were well tolerated. Conclusion: Characterization of the dose-response relationship for VTE and bleeding using an adaptive Phase 2 study design provided a strong quantitative basis for Phase 3 dose selection. © 2013 International Society on Thrombosis and Haemostasis.


Cepeda M.S.,Janssen Research and Development L.L.C. | Berlin J.A.,Janssen Research and Development L.L.C. | Gao C.Y.,Quantitative Solutions Inc. | Wiegand F.,Janssen Global Services L.L.C. | Wada D.R.,Quantitative Solutions Inc.
Pain Medicine | Year: 2012

Objective. To compare placebo responses in neuropathic pain syndromes. Design. Systematic literature review and meta-analysis. Setting and Patients. Randomized placebo-controlled trials assessing pain intensity or pain relief in any neuropathic pain syndrome published since 1995 with ≥5days follow-up. Interventions. Placebo response. Outcome Measures. Pain intensity and responder rates (proportion reporting ≥50% pain relief). Meta-regression models were built. Results. Ninety-four studies (N=5,317) were included in the pain intensity analysis; 47 studies (N=3,087) were included in the responder analysis. After controlling for potential confounders (e.g., subject characteristics, study design characteristics), the placebo response was found to be large and varied with the pain syndrome. Compared with diabetic neuropathic/polyneuropathic pain (DPN), the placebo response for a decline in pain intensity and responder rate was smaller in trials that assessed central pain and postherpetic neuralgia (PHN) and larger in trials that assessed HIV pain. The model-predicted mean decrease (95% confidence interval [CI]) from baseline in pain intensity (0-10 scale) was as follows: DPN, 1.45 (1.35 to 1.55); PHN, 1.16 (1.03 to 1.29); central pain, 0.44 (-0.41 to 1.30); HIV pain, 1.82 (1.51 to 2.12). The predicted responder rates (95% CI) were as follows: DPN, 20% (14.6 to 25.8); PHN, 11.5% (8.4 to 14.5); central pain, 7.2% (2.1 to 12.3); HIV pain, 42.8% (34.9 to 50.7). The type of treatment in the active arm also influenced the placebo response. Conclusions. Placebo response is influenced by the pain syndrome evaluated. These differences should be considered when evaluating novel compounds for the treatment of neuropathic pain conditions. Wiley Periodicals, Inc..


Mandema J.W.,Quantitative Solutions Inc. | Salinger D.H.,Amgen Inc. | Baumgartner S.W.,Amgen Inc. | Baumgartner S.W.,Arrdea Biosciences Inc. | Gibbs M.A.,Amgen Inc.
Clinical Pharmacology and Therapeutics | Year: 2011

We present a dose-response meta-analysis to quantify relative efficacy of biologic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). There is a strong rationale for this analysis because, although multiple biologics are available, information on head-to-head comparisons is limited. Data on the percentage of patients attaining American College of Rheumatology (ACR) 20, 50, and 70 responses were extracted from 50 randomized controlled trials representing 21,500 patients, five mechanisms of action, and nine biologics. The analysis showed that all tumor necrosis factor inhibitors (anti-TNFs) share the same dose-response relationship for ACR 20, 50, and 70, differing only in potency. Yet there are significant differences in efficacy among the anti-TNFs due to differences in the clinical dose ranges available. At the suggested starting dose, golimumab was the least efficacious, followed by infliximab, adalimumab, etanercept, and certolizumab. Significant differences in the dose-response relationship were found between anti-TNFs and other biologics, resulting in differences in efficacy and differential impact of dose titration. © 2011 American Society for clinical Pharmacology and Therapeutics.


Naik H.,Takeda Global Research and Development Center Inc. | Lu J.,Quantitative Solutions Inc. | Cao C.,Takeda Global Research and Development Center Inc. | Pfister M.,Quantitative Solutions Inc. | And 2 more authors.
CPT: Pharmacometrics and Systems Pharmacology | Year: 2013

The G-protein-coupled receptor 40 agonist (GPR40) TAK-875 is being developed as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Pharmacometric approaches such as model-based exposureresponse and meta-analyses were applied to (i) characterize exposure/dose-efficacy responses of TAK-875, (ii) characterize the time course of glycosylated hemoglobin A1c (HbA1c) response with TAK-875 6.25 to 200 mg q.d. doses for 12 weeks, (iii) project and compare HbA1c response with dipeptidyl peptidase 4 (DPP-4) inhibitors and TAK-875 up to 24 weeks, and (iv) provide a quantitative rationale for dose selection in phase 3. On the basis of phase 2 data, relationships between TAK-875 concentrations and HbA1c were well characterized by exposure-response models. EC50 and Emax of TAK-875 were estimated to be 3.16 μg/ml and 0.366, respectively. Model-based simulations over 24 weeks indicated that the 25- and 50-mg q.d. doses of TAK-875 achieve efficacy as comparable with or better than that of commonly used antidiabetic agents. © 2013 ASCPT. All rights reserved.


Veniant M.M.,Amgen Inc. | Komorowski R.,Amgen Inc. | Chen P.,Amgen Inc. | Stanislaus S.,Amgen Inc. | And 6 more authors.
Endocrinology | Year: 2012

Fibroblast growth factor 21 (FGF21), a hormone with short half-life, has consistently shown strong pharmacological efficacy. We first assessed the efficacy of murine recombinant FGF21 in C57BL6 lean mice for 5 wk. We then generated a long-acting FGF21 molecule by fusing a Fc to a variant of human recombinant FGF21 (hrFGF21) that contained two engineered mutations [L98R, P171G; Fc-FGF21(RG)] and tested it in C57BL6 diet-induced obese mice and obese rhesus monkeys. We compared its metabolic properties with those of the hrFGF21. Groups of diet-induced obese mice were treated for 36 d with different doses of hrFGF21 (01, 0.3, and 1 mg/kg twice daily) and with Fc-FGF21(RG) (2.3 mg/kg, every 5 d). Body weight, glucose, insulin, cholesterol, and triglyceride levels were decreased after treatment with either compound. A glucose tolerance test (GTT) was also improved. Obese rhesus monkeys were treated with hrFGF21 (once a day) and Fc-FGF21(RG) (once a week) in a dose-escalation fashion. Doses started at 0.1 and 0.3 mg/kg and ended at 3 and 5 mg/kg for hrFGF21 and Fc-FGF21(RG), respectively. Doses were escalated every 2 wk, and animals were followed up for a washout period of 3 wk. Body weight, glucose, insulin, cholesterol, and triglyceride levels and the GTT profile were decreased to a greater extent with Fc-FGF21(RG) than with hrFGF21. The PK-PD relationship of Fc-FGF21(RG) exposure and triglyceride reduction was also conducted with a maximum response model. In conclusion, in more than one species, Fc-FGF21(RG) chronically administered once a week showed similar or greater efficacy than hrFGF21 administered daily. Copyright © 2012 by The Endocrine Society.


Nakai K.,Chugai Pharmaceutical Co. | Wada R.,Quantitative Solutions Inc. | Iida S.,Chugai Pharmaceutical Co. | Kawanishi T.,Chugai Pharmaceutical Co. | Matsumoto Y.,Nihon University
Drug Metabolism and Pharmacokinetics | Year: 2014

Orlistat is used clinically worldwide as anti-obesity drug. It is a chemically synthesized hydrogenated derivative of lipstatin and is an inhibitor of gastric and pancreatic lipases. It has been found to reduce the absorption of dietary fat in the gastrointestinal tract. Modeling and simulation based on pharmacokinetic/pharmacodynamic analysis is becoming increasingly used in the design of clinical trials to assure that the trials are of high quality and are conducted efficiently. We developed a clinical trial simulation model for orlistat based on Phase III clinical study data. This innovative weight loss model includes the relationships between orlistat dose, changes in fecal fat excretion, and weight loss, and also incorporates a dropout function. The model guided the dose-finding strategy and allowed simulation of long-term clinical outcomes of orlistat. Copyright © 2014 by the Japanese Society for the Study of Xenobiotics (JSSX).


Mandema J.W.,Quantitative Solutions Inc. | Gibbs M.,Amgen Inc. | Boyd R.A.,Pfizer | Wada D.R.,Quantitative Solutions Inc. | Pfister M.,Quantitative Solutions Inc.
Clinical Pharmacology and Therapeutics | Year: 2011

High development cost, low development success, cost-disciplined health-care policies, and intense competition demand an efficient drug development process. New compounds need to bring value to patients by being safe, efficacious, and cost-effective as compared with existing treatment options. Model-based meta-analysis (MBMA) facilitates integration and utilization of summary-level efficacy and safety data, providing a quantitative framework for comparative efficacy and safety assessment. 1,2 This Commentary discusses the application and limitations of MBMA in drug development. © 2011 American Society for clinical Pharmacology and Therapeutics.

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