Nivolumab is a human monoclonal antibody that blocks the interaction between PD‐1 programmed death‐1 (PD‐1) and its ligands, PD‐L1 and PD‐L2. Nivolumab demonstrated efficacy in clinical trials for ...various types of cancer. A time‐varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post‐treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure–response (E‐R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E‐R analysis. The results showed that E‐R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E‐R or dose–response relationship than the steady‐state PK metrics.
Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ ...dysfunction, age, genetics) and extrinsic (e.g., drug–drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision‐making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.
Clinical Pharmacology & Therapeutics (2011) 89 2, 259–267. doi:10.1038/clpt.2010.298
Four non‐small‐cell lung cancer (NSCLC) registration trials were utilized to develop models linking survival to risk factors and changes in tumor size during treatment. The purpose was to leverage ...existing quantitative knowledge to facilitate future development of anti‐NSCLC drugs. Eleven risk factors were screened using a Cox model. A mixed exponential decay and linear growth model was utilized for modeling tumor size. Survival times were described in a parametric model. Eastern Cooperative Oncology Group (ECOG) score and baseline tumor size were consistent prognostic factors of survival. Tumor size was well described by the mixed model. The parametric survival model includes ECOG score, baseline tumor size, and week 8 tumor size change as predictors of survival duration. The change in tumor size at week 8 allows early assessment of the activity of an experimental regimen. The survival model and the tumor model will be beneficial for early screening of candidate drugs, simulating NSCLC trials, and optimizing trial designs.
Clinical Pharmacology & Therapeutics (2009); 86, 2, 167–174 doi:10.1038/clpt.2009.64
Pemetrexed in malignant pleural mesothelioma Hazarika, Maitreyee; White, Jr, Robert M; Booth, Brian P ...
Clinical cancer research,
02/2005, Volume:
11, Issue:
3
Journal Article
Peer reviewed
Open access
This report describes the data and analysis leading to the approval of pemetrexed (LY 231514, MTA, Alimta, Eli Lilly and Co., Indianapolis, IN) by the U.S. Food and Drug Administration (FDA) of a New ...Drug Application for the treatment of malignant pleural mesothelioma (MPM).
The FDA review of the efficacy and safety of pemetrexed assessed in a randomized clinical trial of 448 patients with unresectable MPM comparing pemetrexed plus cisplatin with cisplatin alone, as well as preclinical pharmacology and chemistry data, are described. The basis for marketing approval is discussed.
In one randomized, single-blind, multicenter international trial, 226 patients were randomized to the pemetrexed and cisplatin arm and 222 patients were randomized to cisplatin alone. Median survival times were 12.1 months for pemetrexed and cisplatin and 9.3 months for cisplatin (P = 0.021; hazard ratio, 0.766; 95% confidence interval, 0.61-0.96). Myelosuppression, predominantly neutropenia, was the most common toxicity of pemetrexed plus cisplatin. Other common adverse events were fatigue, leucopenia, nausea, dyspnea, vomiting, chest pain, anemia, thrombocytopenia, and anorexia.
Pemetrexed in combination with cisplatin was approved by the FDA on February 4, 2004 for the treatment of patients with MPM whose disease is either unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) intra venous infusion over 10 minutes on day 1 of each 21-day cycle in combination with 75 mg/m(2) cisplatin infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections before the start and during therapy to reduce severe toxicities. Patients should also receive corticosteroids with the chemotherapy to decrease the incidence of skin rash. Approval was based on a demonstration of survival improvement in a single randomized trial. Response rates and time to tumor progression were not included in product labeling because of inconsistencies in assessments among the investigators, independent radiologic reviewers, and the FDA, reflecting the difficulty of radiographic assessments in malignant mesothelioma. Complete prescribing information is available on the FDA Web site at http://www.fda.gov/cder/approval/index.htm.
The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and ...disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.
The purpose of this study was to assess the effect of trial design and data analysis choices on the bias and precision of pharmacokinetic (PK) parameter estimation. NONMEM was used to simulate and ...analyze plasma concentrations collected according to a dense (five samples) or sparse (single-trough samples) sampling scheme for a one-compartment open model with intravenous administration. The results indicated that the bias on estimates of CL with only single-trough data was 17% compared to less than 1% for only dense data. The estimates of CL were improved by fixing all other parameters and estimating only mean and variance of CL (-11% to 1.4%, depending on the estimation method). Adding dense data led to further improvements (-2.3% to 0.3%, depending on further improvements). In these cases, first-order conditional estimation (FOCE) methods resulted in better estimates of CL than first-order (FO) methods. These steps also improved the Bayesian estimates of CL. These studies support the following recommendations: (1) avoid collecting single-trough concentrations unless there is reasonable knowledge about the PK of the drug; (2) if collecting single-trough concentrations is inevitable, avoid estimating all parameters when modeling single-trough concentration data; (3) use prior information by modeling the single-trough concentration data along with dense data from other studies; and (4) use Bayes estimates if the PK model and its parameters are known with reasonable certainty.
We investigated the involvement of calcitonin gene-related peptide (CGRP) in the vasodilatory mechanism of action of nitric oxide (NO) donors. The functional role of CGRP in NO donor-induced ...vasodilation of isolated rat aortic rings was determined by incubating these drugs with and without CGRP
8–37, a selective CGRP receptor antagonist. CGRP
8–37 (0.63 μM) induced rightward shifts in the vasodilatory concentration–response curves for nitroglycerin (NTG), Piloty’s acid (PA), and SIN-1 (linsidomine). The
ec
50 values for NTG, PA, and SIN-1 were increased by 8.3-, 5.2-, and 2.3-fold, respectively (
P < 0.05). The release of CGRP from rat aorta in response to NTG and PA was measured specifically by radioimmunoassay. Thirty-minute incubations of NTG or PA with rat aorta induced 189.5 and 214.6% increases, respectively, in CGRP release when compared with the control (
P < 0.05). The concentration–response curves of sodium nitroprusside (SNP),
S-nitroso-acetylpenicillamine (SNAP), tetranitromethane (TNM), diethylamine NO complex (DEA-NO), and diethylenetriamine/nitric oxide adduct (DETA NONOate) were not inhibited significantly by CGRP
8–37 co-incubation (
P > 0.05). NO donors also were incubated with aortic strips, and NTG and PA alone induced significant formation of hydroxylamine, a NO
- metabolite (232.4 and 364.9%, respectively,
P < 0.05). These results indicate that only NTG and PA, and to a lesser extent SIN-1, stimulate the release of CGRP from the rat aorta, which subsequently contributes to the vasodilatory activity of these agents. The hydroxylamine formation suggests a possible link between NO
- generation and CGRP release from the vascular wall.
1
The role of the vasculature and calcitonin gene‐related peptide (CGRP) in nitroglycerin (NTG)‐mediated platelet inhibition was studied.
2
In vitro incubations of CGRP in whole blood induced a ...dose‐dependent inhibition of platelet aggregation with an IC50 of 62.1 nM.
3
The platelet inhibition induced by CGRP was blocked by co‐incubation of 0.53 μM CGRP8‐37, as well as 30 μM NG‐nitro‐monomethyl‐L‐arginine (L‐NMMA).
4
In a separate group of experiments, 100 nM NTG in rat whole blood (WB) induced platelet inhibition of 6.0±1.3% (mean±s.d.), which was enhanced to 77.6±3.5% by the addition of rat aortic tissue (AT) (P<0.001). The inclusion of CGRP8–37 with NTG and AT in WB reduced platelet inhibition to 31.6±6.8% (P<0.01). Incubation of WB and AT with 30 μM L‐NMMA reduced NTG‐induced inhibition of platelet aggregation to 26.4±4.2% (P<0.001).
5
It is concluded that vascular tissue contributes to the antiplatelet mechanism of action of NTG. Furthermore, NTG apparently evokes the release of CGRP from vascular tissue and this neuropeptide contributes to the antiplatelet actions of NTG.
6
The antiplatelet activity of CGRP in whole blood is mediated primarily through the activation of nitric oxide synthase.
British Journal of Pharmacology (1997) 122, 577–583; doi:10.1038/sj.bjp.0701408
We tested whether or not platelet inhibition by sodium nitroprusside (SNP) was enhanced by vascular tissue production of nitric oxide (NO) and calcitonin gene-related peptide (CGRP) release. Platelet ...aggregation was determined with whole blood impedance aggregometry after incubations of SNP in the presence or absence of rat aortic tissue (AT) or AT + CGRPS(8-37) (a specific CGRP antagonist). SNP alone had no effect on platelet aggregation until 100 microM was used (2.3 + 1.5 omega vs. control aggregation of 9.9 +/- 2.0 omega; p < 0.001). Co-incubation of AT with SNP significantly enhanced platelet inhibition at 1 (1.6 +/- 1.3 omega; p < 0.001), 10 (0.7 +/- 0.4 omega; p < 0.001), and 100 microM (0.3 +/- 0.3 omega; p < 0.001). CGRP(8-37) did not significantly antagonize aggregation by SNP + AT (p > 0.05). The inhibition of platelet aggregation by 10 microM SNP was inhibited by methylene blue (MB) (9.0 +/- 1.7 omega at 10 microM; 11.7 +/- 2.4 omega at 100 microM; p < 0.001) but not by 30 microM L-N(upsilon)-monomethyl-L-arginine (L-NMMA; 2.9 +/- 1.8 omega; p > 0.05). These results indicate that vascular tissue significantly contributes to the ability of SNP to inhibit platelet aggregation, probably through greater vascular enzymatic production of NO, but not by releasing CGRP, in contrast to nitroglycerin.
Pharmacodynamics of In Vivo Nitrate Action Fung, Ho-Leung; Booth, Brian P; Bauer, John Anthony
The American journal of cardiology,
1998, Volume:
81, Issue:
1
Journal Article, Conference Proceeding
Peer reviewed
We have used animal models to examine the dynamic events associated with the hemodynamic and antiaggregatory actions of nitroglycerin. For the study of hemodynamics, we utilized a rat model of ...congestive heart failure and showed that the major features of nitrate tolerance and withdrawal rebound could be reproduced in this model. We showed that both phenomena can be described quantitatively by a pharmacokinetic/pharmacodynamic model that incorporated rate constants for a number of physiologic rate processes. The model assumes that tolerance is produced by the development of a counterregulatory vasoconstriction, the magnitude of which is dependent on the extent of the vasodilative component of nitrate action. Dissipation of the vasoconstrictive process is shown to be slower than that of nitrate-induced vasodilation. We further showed, in a normal conscious rat model, that the time–courses of the antiaggregatory actions of nitroglycerin are dissociated from those of hemodynamic tolerance, indicating that sustained antiaggregatory action from nitrates is present despite the observation of hemodynamic tolerance. Our experimental findings are generally consistent with clinical results obtained by other investigators. These results indicate that useful information can be gained from pharmacodynamic examination of in vivo nitrate tolerance in experimental animals.
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