Exposure-response Analysis Research Articles

Pharmacometric Analysis to Describe Pharmacokinetics and Exposure-Efficacy Response of Ivermectin in Adolescents Infected with Trichuris trichiura.

The efficacy of the combination therapy of albendazole and ivermectin against Trichuris trichiura infection is higher in Tanzania than in Côte d'Ivoire. This study therefore aimed to investigate the difference between the population pharmacokinetics (PK) at these study sites and to determine if an exposure-response analysis could explain the low efficacy of the combination therapy in Côte d'Ivoire. Twenty-four participants (aged 12-19 years) receiving single doses of ivermectin (200 µg/kg) and albendazole (400 mg) were included in the population PK modeling. A regression analysis was performed to investigate the relationship between the reduction of fecal whipworm eggs and different exposure metrics (peak concentration, area under the plasma drug concentration-time curve [AUC], and time above a certain threshold). The PK profile of ivermectin was best described by a one-compartment model, first-order absorption, and no delay in absorption, with the absorption rate constant estimated as 0.26 per h, an apparent volume of distribution of 162.43 L, and an apparent clearance of 7.82 L/h. In Tanzania, all patients showed a very high reduction in egg count independent of exposure. In Côte d'Ivoire, a relationship was found between higher ivermectin exposure and egg reduction, although not statistically significant. There was no significant difference between the PK profiles at both study sites, despite a difference in clinical outcome. Model-based simulations indicate that higher ivermectin doses such as 400 and 600 µg/kg may be associated with reduced egg count. Larger clinical studies are warranted to explore further the exposure-efficacy response relationship at 200 µg/kg and higher ivermectin doses in adults and children.

Population Pharmacokinetic Modeling and Exposure-Response Analysis for the Antibody-Drug Conjugate Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Carcinoma.

Enfortumab vedotin is a fully human monoclonal antibody directed to Nectin-4 and conjugated to monomethyl auristatin E (MMAE), approved for treatment of previously treated locally advanced or metastatic urothelial carcinoma (mUC). This population analysis characterized pharmacokinetics of enfortumab vedotin and free (unconjugated) MMAE, identified covariates affecting pharmacokinetics, and evaluated weight-based dosing for enfortumab vedotin. Exposure-response analyses characterized relationships between enfortumab vedotin and free MMAE exposures and efficacy/safety endpoints. Data from 748 patients with locally advanced or mUC in 5 clinical studies were analyzed using nonlinear mixed-effects modeling. Patients received enfortumab vedotin 0.50-1.25 mg/kg every 3 weeks or on days 1, 8, and 15 of a 28-day cycle. Relevant covariates retained in final models were evaluated for clinical relevance to enfortumab vedotin and free MMAE exposures. Although some covariates produced differences in exposure, the magnitude of changes was not clinically meaningful. Simulations indicated weight-based dosing yielded more consistent exposures across body weight groups vs. a hypothetical fixed-dose regimen of enfortumab vedotin 95 mg (calculated for median body weight, 75 kg). Exposure-response analysis showed average enfortumab vedotin concentrations were not a statistically significant predictor of overall survival (hazard ratio 0.91, 95% confidence interval: 0.72-1.14; P = 0.41); all exposure quartiles had a greater median overall survival than chemotherapy (11.0-12.6 vs. 9.0 months). Enfortumab vedotin and free MMAE exposures were statistically significant predictors of grade ≥ 3 treatment-related adverse events (both P < 0.0001). This analysis supports enfortumab vedotin 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle.

Exposure-Response Analysis of Tofacitinib in Active Psoriatic Arthritis: Results from Two Phase 3 Studies.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). These post hoc exposure-response (E-R) analyses of pooled data from two Phase 3 studies (NCT01877668 and NCT01882439) characterized the relationships between tofacitinib exposure and efficacy (American College of Rheumatology [ACR] criteria), and changes in hemoglobin (Hgb) in patients with PsA. Efficacy data for the proportion of patients receiving tofacitinib 5 or 10 mg twice daily, or placebo, achieving ACR ≥20%, ≥50%, or ≥70% response criteria (ACR20, ACR50, and ACR70, respectively) at Month 3, were modeled jointly using a four-category ordered categorical exposure-response model (ACR20 non-responder, ACR20 responder but not ACR50 responder, ACR50 responder but not ACR70 responder, and ACR70 responder). A maximum drug effect (Emax) model (using average concentrations of tofacitinib at steady state [Cavg]) adequately described the exposure-ACR response rate relationship. Model-predicted response rates for tofacitinib 5 and 10 mg twice daily were 51% and 58%, respectively, for ACR20; 29% and 36% for ACR50; and 15% and 20% for ACR70. The E-R relationship between tofacitinib exposure and changes in Hgb was assessed using an indirect response model, which generally predicted Hgb concentration-time profiles across treatments well. The proportions of patients experiencing a decrease in Hgb of >2 g/dL were similar with tofacitinib 5 mg twice daily or placebo. These results were generally consistent with previous analyses in rheumatoid arthritis and psoriasis, and support the use of tofacitinib 5 mg twice daily for active PsA.

Automated Poisson regression exposure-response analysis for binary outcomes with PoissonERM.

PoissonERM is an R package used to conduct exposure-response (ER) analysis on binary outcomes for establishing the relationship between exposure and the occurrence of adverse events (AE). While Poisson regression could be implemented with glm(), PoissonERM provides a simple way to semi-automate the entire analysis and generate an abbreviated report as an R markdown (Rmd) file that includes the essential analysis details with brief conclusions. PoissonERM processes the provided data set using the information from the user's control script and generates summary tables/figures for the exposure metrics, covariates, and event counts of each endpoint (each type of AE). After checking the incidence rate of each AE, the correlation, and missing values in each covariate, an exposure-response model is developed for each endpoint based on the provided specifications. PoissonERM has the flexibility to incorporate and compare multiple scale transformations in its modeling. The best exposure metric is selected based on a univariate model's p-value or deviance ( ) as specified. If a covariate search is specified in the control script, the final model is developed using backward elimination. PoissonERM identifies and avoids highly correlated covariates in the final model development of each endpoint. Predicting event incidence rates using external (simulated) exposure metric data is an additional functionality in PoissonERM, which is useful to understand the event occurrence associated with certain dose regimens. The summary outputs of the cleaned data, model developments, and predictions are saved in the working folder and can be compiled into a HTML report using Rmd.

Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships

This work aimed to characterize the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to identify venetoclax doses to be administered to pediatric patients in the phase 3 study. Data from 121 patients across three phase 1 studies enrolling pediatric patients with R/R malignancies were utilized to develop a population pharmacokinetic model to describe venetoclax pharmacokinetics in pediatric patients. Individual patient average venetoclax plasma concentration up to the event of interest, derived based on the population pharmacokinetics analysis, was used to evaluate the exposure-response relationships to efficacy (complete response) and safety (neutropenia and thrombocytopenia) endpoints for patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine (n = 36). The population pharmacokinetic model was then used to simulate exposures in pediatric age- and weight-based subgroups to identify the venetoclax doses for pediatric patients. The pharmacokinetic data were adequately described by the two-compartment population pharmacokinetic model with first-order absorption and elimination. The model accounted for cytochrome P450 3A developmental changes using a maturation function and incorporated allometric scaling to account for growth and body size effect. Weight was identified as a statistically significant covariate on clearance and volume of distribution and retained in the final model. Population pharmacokinetic estimates were comparable to previously reported estimates in adults. Exposure-response analyses suggested that the clinical efficacy of venetoclax in combination with high-dose cytarabine (HDAC) is maximized at 600 mg adult-equivalent, and higher doses are unlikely to enhance clinical efficacy. Venetoclax 600 mg adult-equivalent was selected for further development in combination with HDAC. Additionally, venetoclax 400 mg adult-equivalent was selected for bridging/maintenance therapy in combination with azacitidine. Flat exposure-response relationships were observed with Grade ≥3 neutropenia and thrombocytopenia. Doses were selected based on weight (allometric scaling) for children aged ≥2 years old and based on weight and CYP3A ontogeny for children aged <2 years. The selected age- and weight-based dosing scheme of venetoclax is projected to achieve venetoclax exposures in pediatric subgroups comparable to those observed in adults receiving venetoclax 400 mg or 600 mg. This work characterized the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients and guided the selection of pediatric dosing regimens in support of the venetoclax phase 3 trial in pediatric AML (NCT05183035). NCT03236857, NCT03181126, and NCT03194932.

P1.13A.12 Exposure-Response Analyses to Support Ph3 Dose Selection for I-Dxd (Ifinatamab Deruxtecan) in Extensive Stage SCLC Patients

P1.13A.12 Exposure-Response Analyses to Support Ph3 Dose Selection for I-Dxd (Ifinatamab Deruxtecan) in Extensive Stage SCLC Patients

Road-traffic noise exposure and coronary atherosclerosis in the Swedish CArdioPulmonary bioImage Study (SCAPIS).

Road-traffic noise may influence the development of cardiovascular events such as stroke and myocardial infarction, but etiological mechanisms remain unclear. This study aimed to assess the relationship between long-term road-traffic noise exposure and coronary atherosclerosis in Sweden. In the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort, including 30,154 subjects aged 50-65 years, recruited between 2013 and 2018, coronary atherosclerosis was measured based on computer tomography (CT) scans as coronary artery calcium score, segment involvement score (SIS), and non-calcified plaques (NCP) at enrollment. Based on modified Nordic model, road-traffic noise exposure was modeled for 2000, 2013, and 2018 with interpolation for intermediate years. We investigated the association between time-weighted long-term exposure to road-traffic noise (Lden) and the prevalence of atherosclerosis using ordinal logistic regression models adjusting for potential socioeconomic, behavioral, and environmental confounders, including air pollution. No clear associations were found between road-traffic noise and coronary atherosclerosis. The odds ratio for coronary artery calcium score was 1.00 (95% confidence interval [CI] = 0.96, 1.04), SIS 0.99 (0.96, 1.03), and NCP 0.98 (0.90, 1.03) per interquartile range (9.4 dB Lden) for road-traffic noise exposure during 10 years before enrollment. No consistent associations were observed in site-specific analyses or using shorter exposure periods. Furthermore, exposure-response analyses revealed no clear trends, and there were no strong interactions between road-traffic noise and cardiovascular risk factors in relation to the atherosclerosis markers. Long-term exposure to road-traffic noise was not linked to coronary atherosclerosis or calcification in relatively healthy, middle-aged populations in Sweden.

Pharmacodynamic Exposure-Response Analysis of Fracture Count Data Following Treatment with Burosumab in Patients with XLH.

X-linked hypophosphatemia (XLH) is a rare genetic disorder caused by excessive fibroblast growth factor 23 (FGF23), leading to low serum phosphate levels resulting in increased risk of fractures and pseudofractures. Burosumab is indicated for the treatment of XLH. In this work, we aimed to understand the quantitative relationship between burosumab-treatment-induced improvements in serum phosphate and reduction in fracture and pseudofracture counts in adults with XLH. Burosumab pharmacokinetic pharmacodynamic data from nine clinical studies were first utilized to update a prior population pharmacokinetic pharmacodynamic (PPKPD) model. The updated PPKPD model predictions for serum phosphate exposures along with other factors (i.e., time and treatment) were utilized to evaluate the relationship on fracture counts using Poisson model. The updated PPKPD model suggested that burosumab concentrations required for 50% of maximal effect decreased with increasing baseline serum phosphate levels. A Poisson model with time from baseline, average serum phosphate, and burosumab treatment described the time-varying fracture and pseudofracture count data appropriately. The model suggested a baseline rate of fracture and pseudofracture of 1.87 counts. The model predicted that fracture counts decrease by 1% each week, and by 23% with each unit increase (1.0 mg/dL) in average serum phosphate from lower limit of normal (2.5 mg/dL). An additional 1% decrease in fracture count each week was attributed to burosumab treatment that could not be explained by improvements in serum phosphate. Overall, the model quantified the relationship between burosumab-treatment-induced serum phosphate improvements and reduction in fracture and pseudofracture counts in patients with XLH over time.

Population pharmacokinetics and exposure-response relationships of maribavir in transplant recipients with cytomegalovirus infection.

Maribavir is approved for management of post-transplant cytomegalovirus (CMV) infections refractory and/or resistant to CMV therapies at a dose of 400mg twice daily (BID). Population pharmacokinetic (PopPK) and exposure-response analyses were conducted to support the appropriateness of 400mg BID dosing. A PopPK model was developed using non-linear mixed-effects modeling with pooled maribavir plasma concentration-time data from phase 1 and 2 studies (from 100mg up to 1200mg as single or repeated doses) and the phase 3 SOLSTICE study (400mg BID). Exposure-response analyses were performed for efficacy, safety, and viral resistance based on data collected in the SOLSTICE study. Maribavir PK after oral administration was adequately described by a two-compartment model with first-order elimination, first-order absorption, and an absorption lag-time. There was no evidence that maribavir PK was affected by age, sex, race, diarrhea, vomiting, disease characteristics, or concomitant use of histamine H2 blockers, or proton pump inhibitors. In the SOLSTICE study, higher maribavir exposure was not associated with increased probability of achieving CMV DNA viremia clearance, nor with reduced probability of treatment-emergent maribavir-resistant CMV mutations. A statistically significant association with maribavir exposure was identified for taste disturbance, fatigue, and treatment-emergent serious adverse events, while transplant type, enrollment region, CMV DNA level at baseline, and/or CMV resistance at baseline were identified as additional risk factors for these safety outcomes. In conclusion, the findings of these PopPK and exposure-response analyses provide further support for the recommended maribavir dose of 400mg BID.

Population Pharmacokinetics and Exposure–Response Analysis of a Fixed‐Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults

Trichuris trichiura is a soil‐transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co‐administered with ivermectin. A fixed‐dose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure–response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T. trichiura. Nonlinear mixed‐effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure–response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two‐compartmental model with first‐order absorption and the pharmacokinetics of ivermectin was described using a two‐compartmental model with zero‐order followed by first‐order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure–response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T. trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.

Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.

The advent of new therapeutic modalities highlighted deficiencies in the traditional maximum tolerated dose approach for oncology drug dose selection and prompted the Food and Drug Administration (FDA)'s Project Optimus initiative, which suggests that sponsors take a holistic approach, including efficacy, safety, and pharmacokinetic (PK) and pharmacodynamic data, in conjunction with integrated exposure-response (ER) analyses. However, this method comes with an inherent challenge of the collation of the multisource data. To address this issue, an ER-based clinical utility score (CUS) framework, combining benefit and risk into a single measurement, was developed. Model-predicted outcomes for each clinically relevant end point, informed by ER modeling, are converted to a CUS using a user-defined utility function. Thereafter, individual CUS is integrated into a single score with user-defined weighting for each end point. The user-defined weighting feature allows the user to incorporate expert knowledge/understanding into weighing the product's benefit versus risk profile. To validate the framework, data were leveraged from over 50 oncology programs from 2019 to 2023 on the basis of FDA new drug application/biologics license application review packages and/or related literature studies. Five representative cases were selected for in-depth evaluation. Results showed that the optimal benefit-risk ratio (highest CUS) was consistently observed at PK exposures synonymous with recommended doses. A recurring theme across cases was a greater emphasis on safety over efficacy in oncology drug dose determination. The ER-based CUS framework offers a strategic tool to navigate the complexities of dose selection in oncology programs. It serves as a pillar to the importance of integrative data analysis, aligning with the vision of Project Optimus, and demonstrates its potential in guiding dose optimization by balancing therapeutic benefits against risk.

Informing the Recommended Phase III Dose of Alnuctamab, a CD3 × BCMA T-Cell Engager, Using Population Pharmacokinetics and Exposure-Response Analysis.

Alnuctamab, a B-cell maturation antigen (BCMA)-targeting T-cell engager, has demonstrated encouraging antitumor activity in the phase I study CC-93269-MM-001 treating patients with relapsed or refractory multiple myeloma. Identification of a recommended Phase III dose (RP3D) was a key objective, as such population pharmacokinetic (PopPK) and exposure-response analysis was critical. Intravenous (IV) alnuctamab was administered in fixed doses (0.15-10 mg) or in step-up doses to a maximum 10-mg target dose. Subcutaneous (SC) step-up doses of 3 and 6 mg were followed by a target dose range of 10-60 mg. Concentration data from IV and SC alnuctamab administration was pooled and was well described by a two-compartment PopPK model with first-order absorption and elimination. Covariate analysis determined that the inclusion of baseline soluble BCMA (sBCMA) on clearance significantly improved model fitting. Individual exposure parameters were estimated from the final model to characterize exposure-response relationships. Switching from IV to SC administration improved the safety profile of alnuctamab by limiting the frequency of grade ≥2 CRS events. A significant exposure-CRS relationship was observed after the first SC dose, but not subsequent dose administrations. Exposure-safety analysis did not find a statistically significant relationship between increasing exposure and the probability of key safety events of interest. Logistic regression analysis for patients administered SC alnuctamab identified that increased exposure significantly increased the probability of response, although the additional benefit was minimal at exposures above 30 mg target dose. Considering the totality of exposure-response data, the clinical pharmacology assessment supported a SC RP3D of 3/6/30 mg.

Population pharmacokinetics and exposure-response analyses of safety (ARIA-E and isolated ARIA-H) of lecanemab in subjects with early Alzheimer's disease.

Lecanemab (Leqembi®) was recently approved by health authorities in the United States, Japan, and China to treat early Alzheimer's disease (AD), including patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease upon confirmation of amyloid beta pathology. Extensively and sparsely sampled PK profiles from 1619 AD subjects and 21,929 serum lecanemab observations from two phase I, one phase II, and one phase III studies were well characterized using a two-compartment model with first-order elimination. The final PK model quantified covariate effects of body weight and sex on clearance and central volume of distribution, ADA-positive status, and albumin on clearance, and of Japanese ethnicity on central and peripheral volumes of distribution. Exposure to lecanemab was comparable between two lecanemab-manufacturing processes. However, none of the identified covariates in the model had a clinically relevant impact on model-predicted lecanemab Cmax or AUC at steady state following 10 mg/kg bi-weekly. Importantly, age, a well-recognized risk factor for AD, was not found to significantly affect lecanemab PK. The incidence of ARIA-E as a function of lecanemab exposure was modeled using a logit function with data pooled from 2641 subjects from the phase II and phase III studies, in which a total of 177 incidences of ARIA-E were observed. The probability of ARIA-E was significantly correlated with model-predicted Cmax and predicted to be higher in subjects homozygous for APOE4. The incidence of isolated ARIA-H was not associated with lecanemab exposure and was similar between placebo and lecanemab-treated subjects.

Impact of an Improved Biomass Stove Intervention on Inflammation in a Stepped-wedge Trial in Rural Honduras: Intent-to-treat and Exposure-Response Analyses

Impact of an Improved Biomass Stove Intervention on Inflammation in a Stepped-wedge Trial in Rural Honduras: Intent-to-treat and Exposure-Response Analyses

Population pharmacokinetic and exposure-toxicity analyses of nab-paclitaxel after pegylated recombinant human granulocyte colony-stimulating factor administration in patients with metastatic breast cancer.

This study aimed to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between the concentrations of total and unbound paclitaxel, and the exposure-response analysis of albumin-bound paclitaxel (nab-paclitaxel) after pegylated recombinant human granulocyte colony-stimulating factor (PEG-G-CSF) administration in patients with metastatic breast cancer. A total of 653 concentrations corresponding to total paclitaxel and 334 concentrations corresponding to unbound paclitaxel were analyzed in 24 subjects who randomized received a single 260 mg/m2 dose of two nab-paclitaxel formulations with a 21-35-day washout period. PEG-G-CSF was administered to all the patients in each cycle to prevent neutropenia. The exposure-response relationships were evaluated using the exposure to total, albumin-coated, and unbound paclitaxel, as well as the reduction in neutrophil count. The exposure data were analyzed using nonlinear mixed-effect modeling. A linear regression model was used to test the statistical significance of the correlation between percentage of reduction in neutrophil count and exposure. The PK characteristics of total paclitaxel were described using a three-compartment model with first-order elimination, and a mechanism-based model incorporating linear release of nab-paclitaxel and the saturated binding of unbound paclitaxel to plasma components was established. The release ratio of paclitaxel from nab-paclitaxel was estimated to be 4.60% and the maximum unbound fraction (2.76%) was reached at the end of the infusion. The study found that a longer duration of total paclitaxel concentration > 0.19 µmol/L was significantly correlated with a reduction in neutrophil count (r2 = 0.23, P = 0.00062). Specifically, a duration of > 8.6h was a predictor of a decreased neutrophil count. The decrease in neutrophils induced by nab-paclitaxel was significantly correlated with the duration above a total paclitaxel concentration of 0.19 µmol/L despite the use of PEG-G-CSF.

Model-based population pharmacokinetic and exposure response analyses for safety and efficacy of nivolumab as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer.

Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model-based clinical pharmacology profiling and benefit-risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen. Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure-response (E-R) analyses included data from 756 patients from CheckMate 577. E-R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease-free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune-mediated adverse events (Gr2 + IMAEs) for safety. Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E-R relationships within the exposure range produced by the studied regimen. Model-predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2weeks or 480 mg every 4weeks for 16 weeks followed by 480 mg Q4W up to 1year. The analyses demonstrated a flat E-R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC.

Population pharmacokinetics and exposure-response analyses of SAF-189s in Chinese patients with ALK+/ROS1+ non-small cell lung cancer.

SAF-189s is a potent ALK/ROS1 inhibitor that is currently in clinical development for treating advanced ALK+/ROS1+ non-small cell lung cancer (NSCLC). Comprehensive population pharmacokinetics (PopPK) and exposure-response models were developed to evaluate the efficacy and safety of SAF-189s by integrating data from two clinical studies. The PopPK model was developed using plasma concentration data collected from patients with ALK+/ROS1+ advanced NSCLC (n = 299) and healthy subjects (n = 24). The covariates (demographics, laboratory values, subject types, and concomitant medications) were evaluated to determine their potential influence on the between-patient variability in the pharmacokinetics of SAF-189s. Individual exposure values were then used to investigate the relationships with the efficacy endpoints (overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR)) and key safety endpoints (adverse events of interest). The final PopPK model of SAF-189s was described by a one-compartment model with delayed first-order absorption and time-dependent elimination by allowing the clearance to decrease stepwise over time. Age was included as a covariate for apparent clearance (CL/F), while prior anti-cancer therapy in ALK+ patients (ALKPOT) was included for apparent volume of distribution (V/F). There were no apparent exposure-response relationships for any of the efficacy endpoints at doses of 80-210mg. The relationship between exposure and safety suggested that a higher steady-state exposure was associated with more frequent incidences of hyperglycemia and proteinuria; the 210-mg dose group was also less tolerated than the other low-dose groups. PopPK and exposure-response models were developed for SAF-189s, and their results demonstrate that SAF-189s exposures are at the plateau of exposure-response for efficacy. The 210-mg dose group had a significantly higher safety risk, while the 160-mg dose group was well-tolerated. Thus, 160mg of SAF-189s once daily was selected as the recommended phase III dose for the ALK+/ROS1+ or ROS1+ NSCLC patients.

A joint model of longitudinal pharmacokinetic and time-to-event data to study exposure–response relationships: a proof-of-concept study with alectinib

PurposeIn exposure–response analyses of oral targeted anticancer agents, longitudinal plasma trough concentrations are often aggregated into a single value even though plasma trough concentrations can vary over time due to dose adaptations, for example. The aim of this study was to compare joint models to conventional exposure–response analyses methods with the application of alectinib as proof-of-concept.MethodsJoint models combine longitudinal pharmacokinetic data and progression-free survival data to infer the dependency and association between the two datatypes. The results from the best joint model and the standard and time-dependent cox proportional hazards models were compared. To normalize the data, alectinib trough concentrations were normalized using a sigmoidal transformation to transformed trough concentrations (TTC) before entering the models.ResultsNo statistically significant exposure–response relationship was observed in the different Cox models. In contrast, the joint model with the current value of TTC in combination with the average TTC over time did show an exposure–response relationship for alectinib. A one unit increase in the average TTC corresponded to an 11% reduction in progression (HR, 0.891; 95% confidence interval, 0.805–0.988).ConclusionJoint models are able to give insights in the association structure between plasma trough concentrations and survival outcomes that would otherwise not be possible using Cox models. Therefore, joint models should be used more often in exposure–response analyses of oral targeted anticancer agents.

Pharmacokinetics and Exposure-Response Analyses to Support Dose Selection of Upadacitinib in Crohn's Disease.

Upadacitinib, a selective Janus kinase inhibitor, is the first orally administered therapy approved for the treatment of Crohn's disease (CD). This work characterized the pharmacokinetics of upadacitinib in CD patients and evaluated the relationships between upadacitinib steady-state plasma exposures and efficacy as well as safety parameters during the 12-week induction and the 52-week maintenance periods, to provide dosing recommendations for the treatment of CD. Upadacitinib pharmacokinetics in CD patients administered the extended-release formulation were consistent with patient populations in other approved indications. None of the evaluated CD-specific patient characteristics (e.g., disease location and prior gastrointestinal surgeries) had a meaningful impact on upadacitinib pharmacokinetics. Exposure-response analyses during 12-week induction treatment showed that response across all evaluated efficacy end points were approaching a plateau at median plasma exposures associated with 45 mg QD. Analyses for the maintenance period demonstrated that 30 mg QD is predicted to provide an additional 8% to 10% benefit for endoscopic response and endoscopic remission compared with 15 mg QD in patients who failed biologics. The analyses for safety showed a statistically significant relationship between increasing upadacitinib plasma exposures and the percentage of patients experiencing >2 g/dL decrease in hemoglobin from Baseline during induction and showed shallow relationships for serious infections and herpes zoster during the maintenance period. These results demonstrated adequate absorption of the extended-release formulation of upadacitinib in CD patients. The exposure-response analyses confirmed that 45 mg QD dose maximized efficacy as induction treatment and supported the selection of 15 mg QD or 30 mg QD as the maintenance doses.

Exposure-Response and Subgroup Analyses to Support Body Weight-Based Dosing of Brentuximab Vedotin in Children and Young Adults with Newly Diagnosed High-risk Classical Hodgkin Lymphoma.

The purpose of the study was to evaluate the relationships between brentuximab vedotin (BV) pharmacokinetics, age, and body weight (BW) with efficacy and safety in pediatric and young adult patients with previously untreated, high-risk classical Hodgkin lymphoma in the phase III AHOD1331 study. Overall, 296 patients (age 2-21 years) in the overall population were randomized to and received BV + chemotherapy; the pharmacokinetic subpopulation comprised 24 patients (age <13 years). Age- and/or BW-based (pharmacokinetic surrogates) subgroup analyses of efficacy and safety were conducted for the overall population. Exposure-response analyses were limited to the pharmacokinetic subpopulation. There were no visible trends in disease characteristics across pediatric age subgroups, whereas BW increased with age. Observed antibody-drug conjugate exposures in patients ages <12 years were lower than those in adults administered BV 1.8 mg/kg every 3 weeks, as exposure increased with BW. Nevertheless, no detrimental impact on event-free survival was seen in younger subgroups: 3-year event-free survival rates were 96.2% (2-<12 years) and 92.0% (12-<18 years), with no events observed in those ages <6 years. Neither early response nor lack of need for radiation therapy was associated with high pharmacokinetic exposure. No evidence of exposure-driven grade ≥2 or ≥3 peripheral neuropathy or grade ≥3 neutropenia was seen in exposure-safety and BW-based subgroup analyses; the incidence of these safety events was comparable across pediatric age subgroups, despite lower exposure in younger children. No further adjustments based on age or BW are required for the BV dosage (1.8 mg/kg every 3 weeks) approved in children.