Exposure-response Relationships For Efficacy Research Articles

Population Pharmacokinetic and Exposure-Response Modeling to Inform Risankizumab Dose Selection in Patients With Ulcerative Colitis.

Data from phase IIb/III and phase III studies were used to characterize the population pharmacokinetics of risankizumab and its exposure-response relationships for efficacy and safety in ulcerative colitis (UC) patients. A two-compartment model with first-order absorption and elimination accurately described risankizumab pharmacokinetics. Although certain covariates, namely, body weight, serum albumin, fecal calprotectin, sex, corticosteroid use, advanced therapy inadequate response, and pancolitis, were statistically correlated with risankizumab clearance, their impact on exposure was not clinically meaningful for efficacy or safety. Phase II exposure-response analyses demonstrated that the 1,200 mg intravenous (IV) induction dose at Weeks 0, 4, and 8 achieved near maximal response for all efficacy end points, with suboptimal efficacy from the 600 mg and little added benefit from the 1,800 mg regimens, justifying 1,200 mg IV as the induction dose in the phase III study. Phase III exposure-response analyses for efficacy during induction showed statistically significant exposure-response relationships at Week 12 following 1,200 mg IV at Weeks 0, 4, and 8, in line with phase IIb results. Exposure-response analyses for maintenance demonstrated modest improvement in Week 52 efficacy when increasing the subcutaneous dose from 180 mg to 360 mg with largely overlapping confidence intervals. Exposure-response analyses for safety indicated no apparent exposure-dependent safety events over the induction or maintenance treatment. Based on these results, the recommended dosing regimen for risankizumab in UC patients is 1,200 mg IV at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter.

Effect of Hepatic Impairment on the Pharmacokinetics of Fenfluramine and Norfenfluramine.

Fenfluramine (Fintepla®) is approved for the treatment of seizures associated with the rare epileptic encephalopathies Dravet syndrome and Lennox-Gastaut syndrome. Fenfluramine is extensively metabolized; thus, patients with hepatic impairment (HI) might experience changes in exposure to fenfluramine or its metabolites. In this phase 1 study, we investigated the pharmacokinetics (PK) and safety of a single oral dose of 0.35 mg/kg fenfluramine in subjects with mild (n = 8), moderate (n = 8), or severe (n = 7) HI (Child-Pugh A/B/C, respectively) and healthy control subjects (n = 22) matched for sex, age, and BMI. All subjects underwent serial sampling to determine total plasma concentrations of fenfluramine and its active metabolite, norfenfluramine. Hepatic impairment was associated with increases in fenfluramine exposures, mainly area-under-the-curve (AUC). Geometric least squares mean ratios (90% confidence intervals) for fenfluramine AUC0-∞ in mild, moderate, and severe HI versus healthy controls were 1.98 (1.36-2.90), 2.13 (1.43-3.17), and 2.77 (1.82-4.24), respectively. Changes in exposure to norfenfluramine in mild, moderate, and severe HI were minimal compared with normal hepatic function. Exposures to fenfluramine and norfenfluramine in all HI groups were within the ranges that have been characterized in the overall development program, including ranges examined in exposure-response relationships for efficacy and safety in patients, and determined to have an acceptable safety profile. Mild and moderate HI had a modest effect on fenfluramine exposure that was not clinically meaningful, whereas the higher fenfluramine exposure in severe HI may require dose reduction based on general caution in this population. The modest decrease in norfenfluramine exposure is not considered clinically relevant.

Clinical Pharmacokinetics and Pharmacodynamics of Daratumumab.

Daratumumab is a fully human, monoclonal immunoglobulin G1 and a first-in-class CD38-targeting drug approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory and newly diagnosed multiple myeloma or newly diagnosed light-chain amyloidosis. CD38 is heavily expressed on malignant myeloma cells, and daratumumab exerts anti-myeloma activity via immune-mediated mechanisms, direct induction of apoptosis, and immunomodulation. Daratumumab is used as monotherapy or in combination with standard-of-care myeloma therapies, including proteasome inhibitors, immunomodulatory agents, DNA-alkylating agents, and corticosteroids. Following an intravenous infusion, daratumumab exhibits nonlinear pharmacokinetics (PK), as clearance decreases with higher doses and over time because of target-mediated effects. Dosing schedules vary depending on indications and co-administered drugs, but generally daratumumab is administered weekly for 6-9 weeks followed by a less frequent dosing regimen, once every 2-4 weeks. Daratumumab exposure is strongly correlated with efficacy, and the exposure-efficacy relationship follows a maximal effect model, whereas exposure is not correlated with safety endpoints. The approved dose of 16 mg/kg of daratumumab results in the saturation of 99% of the target at the end of weekly dosing in most patients, and high target saturation is maintained over time during the less frequent dosing schedule. Infusion-related reactions are frequently observed in patients given daratumumab, particularly with the first infusion, thus prompting long durations of infusion (~ 7 h) and splitting of the first dose across 2 days. This led to the development of a subcutaneous delivery formulation for daratumumab (Dara-SC). Dara-SC provides a similar efficacy and safety profile to intravenous daratumumab (Dara-IV) but has a much lower rate of infusion-related reactions and a shorter infusion time. Exposure-response relationships for efficacy and safety endpoints were similar between Dara-SC and Dara-IV, and co-administered drugs with either Dara-IV or Dara-SC do not significantly affect daratumumab PK. Except for baseline myeloma type and albumin level, none of the other investigated disease and patient characteristics (renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group performance status) was identified to have clinically relevant effects on exposure to daratumumab monotherapy or combination therapy regimens. Dara-IV exposure was significantly lower in patients with immunoglobulin G myeloma compared with patients with non-immunoglobulin G myeloma (p < 0.0001) and in patients with a lower albumin level, whereas the overall response rate was similar regardless of the myeloma type and albumin level. Daratumumab dose adjustment is not currently recommended based on disease and patient characteristics.

Population Pharmacokinetic and Exposure-Response Analyses for Efficacy and Safety of Risankizumab in Patients With Active Crohn's Disease.

The population pharmacokinetics (PK) of risankizumab and exposure-response relationships for efficacy and safety in patients with Crohn's disease (CD) were characterized using data from phase II and III studies to support dosing regimen selection. A two-compartment model with first-order absorption and first-order elimination adequately described risankizumab PK. Covariates including sex, baseline fecal calprotectin, corticosteroid use, baseline creatinine clearance, body weight, and baseline albumin were statistically correlated with risankizumab clearance, but their impact on exposure was not clinically relevant for efficacy or safety. Exposure-response analyses showed that exposures associated with the 600 mg intravenous (i.v.) induction dose at Weeks 0, 4, and 8 achieved a near maximal response for all efficacy end points evaluated, with negligible added benefit from the 1,200 mg i.v. regimen. By Week 52 of the maintenance treatment, trends of higher responses were observed for the exposure range associated with the 360 mg subcutaneous (s.c.) every-8-weeks (Q8W) regimen for most of the evaluated efficacy end points, particularly for the more stringent end points, such as endoscopic remission and ulcer-free endoscopy. Exposure-response analyses for safety did not identify any apparent relationship between exposure and safety. These results supported the final dose recommendation of 600 mg i.v. at Weeks 0, 4, and 8, followed by 360 mg s.c. at Week 12 and Q8W thereafter in patients with CD.

Combination dose finding trials for targeted/immuno oncology agents in early development: Lessons learned.

e13595 Background: Combination therapy is commonly evaluated in clinical development of oncology investigational agent (IA). An IA may be combined with an approved agent (AA), or with another IA. The aim of this landscape analysis was to 1) summarize and evaluate the different dose finding study design options used in early clinical development for oncology targeted/immuno therapy combinations; 2) propose best-fit application scenarios for each trial designs. Methods: The data sources included 1) FDA approved oncology combination therapies from 2010 to 2021; 2) registered early-stage oncology combination trials in the US with protocol available at clinicaltrial.gov from 2015 to mid-2021; 3) Pfizer internal programs. This analysis focused on “IA + IA” and “IA + AA” combinations. We extracted data on modality type, target, starting dose rationale, trial design and approved dose (if applicable) of the combination. Starting dose considerations and pros/cons of different trial designs were assessed. Results: Both external and internal in scope trials were summarized, including 8 approved non-Pfizer oncology combinations, 32 clinicaltrial.gov registered external trials and 14 Pfizer internal programs. Most surveyed combination trials included an AA. Selection of starting doses and dose escalation design for the combination were the two critical factors influencing the efficiency of clinical development (time, cost and resources). Overlapping toxicities are key concerns resulting in more conservative combination starting doses. The combination dose finding was generally performed with one of the following designs: sequential design, parallel (staggered) design, healthy volunteer first-in-human single ascending dose before first-in-patient combination and monotherapy lead-in (intra-patient “crossover”). A comparison of the characteristics of these dose finding designs indicate that the choice of a particular design should consider factors including exposure-response relationships for efficacy and safety of both monotherapy and combination, the benefit/risk to trial participants, study population, etc. We proposed application scenarios for each trial designs by incorporating the above considerations and analyzing the collected trial examples in the database. The dose finding for combinations between two IAs should consider additional factors including the relative contributions of the two agents to efficacy and safety, the anticipated minimal dose/exposure level for efficacy, and potential pharmacokinetic/pharmacodynamic drug-drug interactions. Conclusions: Multiple design options for dose finding exist for oncology targeted/immuno therapy combinations involving IA. The choice of a suitable design should consider properties and available data of each agents involved, trial efficiency, as well as benefit/risk of trial participants and target indication.

POS1054 UPADACITINIB PHARMACOKINETICS AND EXPOSURE-RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY IN PSORIATIC ARTHRITIS – ANALYSES OF THE PHASE 3 SELECT-PsA STUDIES

Background:Upadacitinib (UPA) is an oral, reversible, JAK inhibitor approved for the treatment of rheumatoid arthritis (RA). The efficacy and safety profile of UPA in psoriatic arthritis (PsA) has been established in the SELECT-PsA program which includes two global Phase 3 studies.Objectives:These analyses characterize UPA pharmacokinetics and exposure-response relationships for efficacy and safety endpoints using data from the SELECT-PsA studies.Methods:The SELECT-PsA program enrolled patients with prior inadequate response (IR) or intolerance to ≥1 non-bDMARD1 (N=1705) and prior IR or intolerance to ≥1 bDMARD2 (N=642). Data from both trials was integrated for patients receiving placebo (PBO), UPA 15mg once daily (QD) and UPA 30mg QD; adalimumab data was excluded from this analysis. UPA pharmacokinetics were characterized in PsA patients using Bayesian population pharmacokinetics analyses and utilizing prior information from analyses in healthy subjects and RA patients. Exposure-response analyses were conducted using logistic regression to characterize the relationships between upadacitinib average plasma concentration during a dosing interval (Cavg) and the percentage of patients achieving ACR20/50/70 at Weeks 12 and 24, static Investigator Global Assessment of psoriasis (sIGA) of 0 or 1 (clear or almost clear) and at least a 2-point improvement from baseline, and PASI75 at Weeks 16 and 24 or experiencing selected clinically relevant safety events through week 24.Results:Analyses were conducted using data from 1694 subjects (for pharmacokinetics) and 1916 subjects (for exposure-response analyses). UPA model-estimated plasma exposures in subjects with PsA who received 15mg and 30mg QD doses were comparable to previously estimated exposures in subjects with RA. Body weight and methotrexate use had no clinically relevant effects on UPA exposures. There was a statistically significant relationship between UPA Cavg and the percentage of subjects who achieved Week 12 ACR50/70, Week 16 sIGA 0/1, and Week 24 sIGA 0/1 (Figure 1). No statistically significant exposure-response relationship was observed for Week 12 ACR20, Week 16 PASI75, or Week 24 ACR20/50/70 or PASI75, indicating that the 15mg QD exposures are approximately at the plateau of response for these endpoints. No statistically significant relationships were observed between upadacitinib Cavg and the percentage of subjects experiencing pneumonia, herpes zoster, hemoglobin &lt; 8 g/dL, Grade ≥3 lymphopenia, Grade ≥3 neutropenia. There was a shallow but statistically significant exposure-response relationships with the occurrence of serious infections and decrease in hemoglobin from baseline (&gt;2 g/dL and &gt;2 g/dL in combination with hemoglobin &lt; lower limit for normal).Figure 1.Observed and Model Predicted Efficacy Responses at Week 12 (for ACR50/70) or at Weeks 16 and Week 24 (for sIGA 0/1) Versus Upadacitinib Plasma ExposuresConclusion:Exposure-response analyses demonstrated that plasma exposures associated with UPA 15 mg QD achieves robust efficacy in subjects with PsA with limited effects on the evaluated safety endpoints. UPA plasma exposures associated with UPA 15 and 30mg QD are predicted to provide similar ACR responses by week 24 while a small additional efficacy benefit with UPA 30mg is predicted for the achievement sIGA 0/1.

Exposure-response relationships for efficacy and safety of risankizumab in patients with moderate to severe plaque psoriasis: Integrated analyses of phase 2 and 3 clinical trials

Exposure-response relationships for efficacy and safety of risankizumab in patients with moderate to severe plaque psoriasis: Integrated analyses of phase 2 and 3 clinical trials

Sa1764 - Upadacitinib Exposure-Response Relationships for Efficacy in Subjects with Moderately to Severely Active Crohn's Disease - Analysis of Celest Study

Sa1764 - Upadacitinib Exposure-Response Relationships for Efficacy in Subjects with Moderately to Severely Active Crohn's Disease - Analysis of Celest Study

Exposure–response analyses of trastuzumab emtansine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane

In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-free survival (PFS) and overall survival (OS) versus capecitabine plus lapatinib (control) in previously treated human epidermal growth factor receptor 2-positive advanced breast cancer. Using EMILIA data, we evaluated the T-DM1 exposure-response relationship. Exposure-response relationships were examined with four exposure metrics [model-predicted and observed minimum concentration (C min) and area under the concentration-time curve from time zero to day 21 of T-DM1 at cycle 1] and multiple efficacy (OS, PFS, objective response rate) and safety (grade ≥ 3 adverse events, grade ≥ 3 thrombocytopenia, grade ≥ 3 hepatotoxicity) endpoints. An apparent exposure-response trend was observed between model-predicted exposure metrics and efficacy; trends for observed exposure metrics were shallower and often not significant. Although median OS and PFS were numerically longer in patients with higher versus lower model-predicted cycle 1 C min, OS and PFS hazard ratios for T-DM1-treated patients in the lowest exposure quartile (Q1) versus control were < 1 after adjusting for baseline risk factors (e.g., ECOG status, tumor burden, measurable disease, and number of disease sites). No meaningful exposure-response relationship was observed for any safety endpoints. Exposure-response relationships for efficacy were inconsistent across exposure metrics; model-predicted cycle 1 C min showed the strongest exposure-response trend. The Q1 subgroup based on model-predicted cycle 1 C min had numerically similar or better OS and PFS versus control following covariate adjustment. The approved T-DM1 dose (3.6mg/kg every 3weeks) has a positive benefit-risk ratio versus control, even for the T-DM1 Q1 subgroup.

Population pharmacokinetics and pharmacodynamics of dalfampridine-ER in healthy volunteers and in patients with multiple sclerosis

Objective:Using data pooled from several studies of dalfampridine extended release (ER), a population pharmacokinetic model was developed for the purposes of characterizing the population pharmacokinetics and pharmacodynamics of dalfampridine-ER with respect to variability in pharmacokinetics, covariates affecting the pharmacokinetics, and whether the current therapeutic dosage represents an optimal dosage. Studies were conducted in healthy volunteers and multiple sclerosis (MS) patients over the course of development and registration of dalfampridine extended release tablets (dalfampridine-ER [Ampyra]; prolonged-, modified- or sustained-release fampridine [Fampyra] in some countries).Methods:The model used to best describe the population pharmacokinetics of dalfampridine-ER was an open, one-compartment model with first-order absorption, first-order elimination and an absorption lag time.Results:The population median estimated oral clearance was 36 L/h for a 50-year-old woman with a creatinine clearance of 105 mL/min and 42 L/h for a comparable man. The typical volume of distribution was 304 L for women and 403 L for men. The estimated absorption rate constant was 1.22 hours−1 in the fasted state and 2.22 hours−1 when given with food. The covariates identified as having a significant effect (p < 0.01) on model fit were food and gender on absorption rate, and gender, age and creatinine clearance on oral clearance. Only creatinine clearance and age are of clinical relevance. Concomitant medications did not affect any of the parameters in the model. Exposure–response relationships for both efficacy and safety were consistent with what has been observed in clinical trials. Limitations of this study include some reliance on unpublished data, and the limited effectiveness of the model for determining the likelihood of the efficacy and safety of dalfampridine-ER in clinical practice.Conclusions:The approved therapeutic dosage regimen of dalfampridine-ER 10 mg twice daily was identified as the optimum dosing regimen based on model-predicted exposure response relationships for efficacy and adverse events. A limitation of this study is the limited effectiveness of the models used to predict long-term efficacy and safety of dalfampridine-ER in clinical use.