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Papers by Jonathan French

Clinical Pharmacology & Therapeutics, 2022

CPT: Pharmacometrics & Systems Pharmacology, 2021

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

British Journal of Clinical Pharmacology, 2021

To identify linzagolix doses, an oral GnRH receptor antagonist, that effectively lower oestradiol... more To identify linzagolix doses, an oral GnRH receptor antagonist, that effectively lower oestradiol (E2) to relieve endometriosis-related pelvic pain without compromising bone health. Integrated statistical, pharmacokinetic-pharmacodynamic and systems pharmacology models were developed from Phase 1 and 2 clinical trial data in healthy volunteers and patients, receiving linzagolix 25-200 mg daily or placebo, and analysed simultaneously. The main outcome measures were pelvic pain scores for dysmenorrhoea, nonmenstrual pelvic pain (NMPP), uterine bleeding and lumbar spine bone mineral density (BMD). Linzagolix pharmacokinetics were described by a 2-compartment model with sequential zero/first-order absorption process (CL/F: 0.422 L/h). E2 changes over time were well described as a function of linzagolix 24-hour AUC (AUC50 : 1.68 × 105 ng h/mL). For a Caucasian reference patient, a change in E2 from 50-20 pg/mL at 24 weeks increased the odds of relief of dysmenorrhoea 1.33-fold and NMPP 1.07-fold (95% CI: 1.22-1.47 and 1.02-1.12, respectively) and decreased bleeding days by 1.55 (95% CI: 1.39-1.72). A previously validated quantitative systems pharmacology BMD model was adjusted to the clinical data. The mean week 24 lumbar spine BMD change from baseline ranged from -0.092% in the 50 mg dose, -1.30% in the 100 mg dose group and -2.67% in the 200 mg dose group. The previously-reported E2 target range (20-50 pg/mL) to balance efficacy and safety endpoints was confirmed. Linzagolix once daily doses between 75-125 mg daily were expected to meet endometriosis-associated pain, efficacy, and BMD loss targets in Caucasian patients.

CPT: Pharmacometrics & Systems Pharmacology, 2021

This analysis was conducted to assess exposure–response relationships for efficacy and safety of ... more This analysis was conducted to assess exposure–response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (Cavg) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher Cavg coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between Cavg and incidence of ALT‐related and AST‐related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT‐related and AST‐related AEs. These results support the US Food and Drug Administration–approved dose (400 mg two times/day without initial loading dose).

Poster Session Abstracts, 2017

Background: TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trast... more Background: TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) compared to treatment of physician9s choice (TPC) in patients with HER2+ MBC who have progression after at least two regimens of HER2-directed therapy. Population pharmacokinetic (PK) and exposure-response (E-R) analyses were performed to characterize T-DM1 PK as well as E-R relationship for key efficacy and safety endpoints in the population. Methods: Post-hoc analysis based on historical T-DM1 population PK models was performed to assess whether PK is consistent with historical data. E-R analyses with OS and PFS were conducted using Cox proportional hazard (CPH) models with exposure metrics (model-predicted Cycle 1 C min and AUC ss ) included in the model. Logistic regression models were used for binary endpoints of overall response rate (ORR) and key safety endpoints with exposure metrics included as continuous variable only. To supplement the E-R analysis for OS and PFS, case matching analyses were conducted to compare OS and PFS in the lowest exposure quartile (Q1) vs. higher exposure quartiles (Q2-4) to their corresponding matched control. Results: Historical T-DM1 population PK model well described T-DM1 PK in TH3RESA study. In CPH analyses with OS and PFS, hazard ratios (HR) of both efficacy endpoints consistently decreased with increasing T-DM1 exposure. The E-R relationship is supported by case matching analyses, where T-DM1 treated patients were stratified by model-predicted Cycle 1 C min . HRs of OS and PFS for patients at Q2−4 versus their matched TPC patients (HR (95%CI): 0.58 (0.44, 0.78) for OS; 0.47 (0.36, 0.62) for PFS) were numerically smaller than that of T-DM1 treated patients at Q1 versus their corresponding matched TPC patients (HR (95%CI): 0.96 (0.63, 1.47) for OS; 0.92 (0.64, 1.32) for PFS). For ORR, an E-R trend was also noted. On the other hand, no E-R relationship was identified with key safety endpoints. Conclusion: T-DM1 PK in TH3RESA patient population is similar to historical data. Although an E-R relationship was observed for efficacy, the results need to be interpreted with caution given the potential confounding association between risk factor and PK. No E-R relationship was observed for the safety endpoints examined. Citation Format: Chen S-C, Polhamus D, Riggs M, French J, Wang X, Smitt M, Hoersch S, Strasak A, Chernyukhin N, Quartino A, Jin J, Girish S, Li C. Population pharmacokinetics (PK) and exposure-response (E-R) analysis of trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (MBC) who have received at least two prior regimens of HER2-directed therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-26.

Poster Session Abstracts, 2017

Background: TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trast... more Background: TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) compared to treatment of physician9s choice (TPC) in patients with HER2+ MBC who have progression after at least two regimens of HER2-directed therapy. Population pharmacokinetic (PK) and exposure-response (E-R) analyses were performed to characterize T-DM1 PK as well as E-R relationship for key efficacy and safety endpoints in the population. Methods: Post-hoc analysis based on historical T-DM1 population PK models was performed to assess whether PK is consistent with historical data. E-R analyses with OS and PFS were conducted using Cox proportional hazard (CPH) models with exposure metrics (model-predicted Cycle 1 C min and AUC ss ) included in the model. Logistic regression models were used for binary endpoints of overall response rate (ORR) and key safety endpoints with exposure metrics included as continuous variable only. To supplement the E-R analysis for OS and PFS, case matching analyses were conducted to compare OS and PFS in the lowest exposure quartile (Q1) vs. higher exposure quartiles (Q2-4) to their corresponding matched control. Results: Historical T-DM1 population PK model well described T-DM1 PK in TH3RESA study. In CPH analyses with OS and PFS, hazard ratios (HR) of both efficacy endpoints consistently decreased with increasing T-DM1 exposure. The E-R relationship is supported by case matching analyses, where T-DM1 treated patients were stratified by model-predicted Cycle 1 C min . HRs of OS and PFS for patients at Q2−4 versus their matched TPC patients (HR (95%CI): 0.58 (0.44, 0.78) for OS; 0.47 (0.36, 0.62) for PFS) were numerically smaller than that of T-DM1 treated patients at Q1 versus their corresponding matched TPC patients (HR (95%CI): 0.96 (0.63, 1.47) for OS; 0.92 (0.64, 1.32) for PFS). For ORR, an E-R trend was also noted. On the other hand, no E-R relationship was identified with key safety endpoints. Conclusion: T-DM1 PK in TH3RESA patient population is similar to historical data. Although an E-R relationship was observed for efficacy, the results need to be interpreted with caution given the potential confounding association between risk factor and PK. No E-R relationship was observed for the safety endpoints examined. Citation Format: Chen S-C, Polhamus D, Riggs M, French J, Wang X, Smitt M, Hoersch S, Strasak A, Chernyukhin N, Quartino A, Jin J, Girish S, Li C. Population pharmacokinetics (PK) and exposure-response (E-R) analysis of trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (MBC) who have received at least two prior regimens of HER2-directed therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-26.

CPT: Pharmacometrics & Systems Pharmacology, 2021

Journal of Crohn's & colitis, Jan 17, 2017

A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in ... more A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis (UC) or Crohn's disease (CD) has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 (Caverage) as exposure measure. Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship; more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10%...

Wiley StatsRef: Statistics Reference Online, 2014

Alzheimer's & Dementia, 2010

Background: Various authors have evaluated disease progression in Alzheimer's disease (AD), using... more Background: Various authors have evaluated disease progression in Alzheimer's disease (AD), using patient data from individual clinical studies or pooled data across various trials. We conducted a systematic review of public data sources from 1990 to 2008 for all available AChE inhibitor studies, as well as clinical studies that evaluated the rate of deterioration in AD patients. Unique to this analysis, we developed a model based on literature data to describe the longitudinal response in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) (change from baseline) in mild to moderate severity AD patients. The model was used to estimate disease progression for both placebo-treated patients and acetylcholinesterase (AChE)-inhibitor treated patients, and factors that affected disease progression. Methods: We collected 576 mean ADAS-cog changes from baseline data points of 52 trials, representing data from approximately 19,972 patients and more than 84,000 individual observations. The model described the rate of disease progression, the evident placebo effect, and the symptomatic effect of AChE-inhibitors. Baseline ADAS-cog, Mini-Mental State Examination score, age, and year of publication were tested as covariates. Results: The disease progression in mild to moderate AD patients across all available and relevant literature sources was estimated as 5.5 points per year. An Emax-type model best described the symptomatic drug effect of AChE inhibitors. The rate of disease progression (underlying disease progression) was no different between placebo and AChE-inhibitors groups. Baseline ADAS-cog is a significant covariate in disease progression. Baseline age was also tested as a covariate in the rate of disease progression, but the model was unable to describe any effects of age, likely because of the narrow distribution of mean age (literature-level analysis). There was no significant impact of publication year in the model. Conclusions: Baseline ADAS-cog is a significant covariate affecting the rate of disease progression, and it describes or at least explains the different rates of deterioration evident in early or late stages of the disease. There was no significant impact of publication year in the model, suggesting that disease progression has not slowed in more recent trials.

Alzheimer's & Dementia, 2009

Antimicrobial Agents and Chemotherapy, 2016

ABSTRACTInhalational anthrax has high mortality even with antibiotic treatment, and antitoxins ar... more ABSTRACTInhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolizedBacillus anthracisspores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% c...

Journal of Crohn's & colitis, Jan 29, 2018

Cancer chemotherapy and pharmacology, Jan 11, 2017

In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-f... more 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...

Arthritis research & therapy, Jan 15, 2015

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tof... more Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib modulates the signaling of cytokines that are integral to lymphocyte activation, proliferation, and function. Thus, tofacitinib therapy may result in suppression of multiple elements of the immune response. Serious infections have been reported in tofacitinib RA trials. However, limited head-to-head comparator data were available within the tofacitinib RA development program to directly compare rates of serious infections with tofacitinib relative to biologic agents, and specifically adalimumab (employed as an active control agent in two randomized controlled trials of tofacitinib). A systematic literature search of data from interventional randomized controlled trials and long-term extension studies with biologics in RA was carried out. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results of the review and meta...

Objectives: Association of Vitamin D3 (D3) and its metabolite (25OHD3) exposure with various dise... more Objectives: Association of Vitamin D3 (D3) and its metabolite (25OHD3) exposure with various diseases, including bone health, diabetes, and cancer, has become an active area of research[1]. Clinical studies investigating these relationships with D3 and 25OHD3 vary in dosing regimen, assays, demographics, and control of endogenous D3 production. This leads to uncertain and conflicting exposure-related associations with D3 and 25OHD3. To elucidate this parent-metabolite system, a population PK (PPK) model was developed to predict D3 and 25OHD3 from varied doses and administration routes. Sources of variability related to 25OHD3 baseline (BL), weight (WT), and assay type were explored. Methods: Public source PK data pertaining to D3 and 25OHD3 in healthy or osteoporotic populations, including 57 studies representing 5406 individuals (25 individual-level and 122 group-level units), were selected using specified search criteria in PUBMED. Data included IV, oral, single and multiple dose ...

Clinical Pharmacology & Therapeutics, 2006

BACKGROUND/AIMS: Drug-induced QT interval prolongation, which can lead to torsade de pointes, is ... more BACKGROUND/AIMS: Drug-induced QT interval prolongation, which can lead to torsade de pointes, is a concern in drug development. The present study evaluated the predictability of nonclinical assays (in vitro hERG and in vivo safety pharmacology studies) for drug-induced QT interval prolongation.

Clinical Pharmacology & Therapeutics, 2022

CPT: Pharmacometrics & Systems Pharmacology, 2021

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

British Journal of Clinical Pharmacology, 2021

To identify linzagolix doses, an oral GnRH receptor antagonist, that effectively lower oestradiol... more To identify linzagolix doses, an oral GnRH receptor antagonist, that effectively lower oestradiol (E2) to relieve endometriosis-related pelvic pain without compromising bone health. Integrated statistical, pharmacokinetic-pharmacodynamic and systems pharmacology models were developed from Phase 1 and 2 clinical trial data in healthy volunteers and patients, receiving linzagolix 25-200 mg daily or placebo, and analysed simultaneously. The main outcome measures were pelvic pain scores for dysmenorrhoea, nonmenstrual pelvic pain (NMPP), uterine bleeding and lumbar spine bone mineral density (BMD). Linzagolix pharmacokinetics were described by a 2-compartment model with sequential zero/first-order absorption process (CL/F: 0.422 L/h). E2 changes over time were well described as a function of linzagolix 24-hour AUC (AUC50 : 1.68 × 105 ng h/mL). For a Caucasian reference patient, a change in E2 from 50-20 pg/mL at 24 weeks increased the odds of relief of dysmenorrhoea 1.33-fold and NMPP 1.07-fold (95% CI: 1.22-1.47 and 1.02-1.12, respectively) and decreased bleeding days by 1.55 (95% CI: 1.39-1.72). A previously validated quantitative systems pharmacology BMD model was adjusted to the clinical data. The mean week 24 lumbar spine BMD change from baseline ranged from -0.092% in the 50 mg dose, -1.30% in the 100 mg dose group and -2.67% in the 200 mg dose group. The previously-reported E2 target range (20-50 pg/mL) to balance efficacy and safety endpoints was confirmed. Linzagolix once daily doses between 75-125 mg daily were expected to meet endometriosis-associated pain, efficacy, and BMD loss targets in Caucasian patients.

CPT: Pharmacometrics & Systems Pharmacology, 2021

This analysis was conducted to assess exposure–response relationships for efficacy and safety of ... more This analysis was conducted to assess exposure–response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (Cavg) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher Cavg coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between Cavg and incidence of ALT‐related and AST‐related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT‐related and AST‐related AEs. These results support the US Food and Drug Administration–approved dose (400 mg two times/day without initial loading dose).

Poster Session Abstracts, 2017

Background: TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trast... more Background: TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) compared to treatment of physician9s choice (TPC) in patients with HER2+ MBC who have progression after at least two regimens of HER2-directed therapy. Population pharmacokinetic (PK) and exposure-response (E-R) analyses were performed to characterize T-DM1 PK as well as E-R relationship for key efficacy and safety endpoints in the population. Methods: Post-hoc analysis based on historical T-DM1 population PK models was performed to assess whether PK is consistent with historical data. E-R analyses with OS and PFS were conducted using Cox proportional hazard (CPH) models with exposure metrics (model-predicted Cycle 1 C min and AUC ss ) included in the model. Logistic regression models were used for binary endpoints of overall response rate (ORR) and key safety endpoints with exposure metrics included as continuous variable only. To supplement the E-R analysis for OS and PFS, case matching analyses were conducted to compare OS and PFS in the lowest exposure quartile (Q1) vs. higher exposure quartiles (Q2-4) to their corresponding matched control. Results: Historical T-DM1 population PK model well described T-DM1 PK in TH3RESA study. In CPH analyses with OS and PFS, hazard ratios (HR) of both efficacy endpoints consistently decreased with increasing T-DM1 exposure. The E-R relationship is supported by case matching analyses, where T-DM1 treated patients were stratified by model-predicted Cycle 1 C min . HRs of OS and PFS for patients at Q2−4 versus their matched TPC patients (HR (95%CI): 0.58 (0.44, 0.78) for OS; 0.47 (0.36, 0.62) for PFS) were numerically smaller than that of T-DM1 treated patients at Q1 versus their corresponding matched TPC patients (HR (95%CI): 0.96 (0.63, 1.47) for OS; 0.92 (0.64, 1.32) for PFS). For ORR, an E-R trend was also noted. On the other hand, no E-R relationship was identified with key safety endpoints. Conclusion: T-DM1 PK in TH3RESA patient population is similar to historical data. Although an E-R relationship was observed for efficacy, the results need to be interpreted with caution given the potential confounding association between risk factor and PK. No E-R relationship was observed for the safety endpoints examined. Citation Format: Chen S-C, Polhamus D, Riggs M, French J, Wang X, Smitt M, Hoersch S, Strasak A, Chernyukhin N, Quartino A, Jin J, Girish S, Li C. Population pharmacokinetics (PK) and exposure-response (E-R) analysis of trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (MBC) who have received at least two prior regimens of HER2-directed therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-26.

Poster Session Abstracts, 2017

Background: TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trast... more Background: TH3RESA was a Phase III randomized study to evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) compared to treatment of physician9s choice (TPC) in patients with HER2+ MBC who have progression after at least two regimens of HER2-directed therapy. Population pharmacokinetic (PK) and exposure-response (E-R) analyses were performed to characterize T-DM1 PK as well as E-R relationship for key efficacy and safety endpoints in the population. Methods: Post-hoc analysis based on historical T-DM1 population PK models was performed to assess whether PK is consistent with historical data. E-R analyses with OS and PFS were conducted using Cox proportional hazard (CPH) models with exposure metrics (model-predicted Cycle 1 C min and AUC ss ) included in the model. Logistic regression models were used for binary endpoints of overall response rate (ORR) and key safety endpoints with exposure metrics included as continuous variable only. To supplement the E-R analysis for OS and PFS, case matching analyses were conducted to compare OS and PFS in the lowest exposure quartile (Q1) vs. higher exposure quartiles (Q2-4) to their corresponding matched control. Results: Historical T-DM1 population PK model well described T-DM1 PK in TH3RESA study. In CPH analyses with OS and PFS, hazard ratios (HR) of both efficacy endpoints consistently decreased with increasing T-DM1 exposure. The E-R relationship is supported by case matching analyses, where T-DM1 treated patients were stratified by model-predicted Cycle 1 C min . HRs of OS and PFS for patients at Q2−4 versus their matched TPC patients (HR (95%CI): 0.58 (0.44, 0.78) for OS; 0.47 (0.36, 0.62) for PFS) were numerically smaller than that of T-DM1 treated patients at Q1 versus their corresponding matched TPC patients (HR (95%CI): 0.96 (0.63, 1.47) for OS; 0.92 (0.64, 1.32) for PFS). For ORR, an E-R trend was also noted. On the other hand, no E-R relationship was identified with key safety endpoints. Conclusion: T-DM1 PK in TH3RESA patient population is similar to historical data. Although an E-R relationship was observed for efficacy, the results need to be interpreted with caution given the potential confounding association between risk factor and PK. No E-R relationship was observed for the safety endpoints examined. Citation Format: Chen S-C, Polhamus D, Riggs M, French J, Wang X, Smitt M, Hoersch S, Strasak A, Chernyukhin N, Quartino A, Jin J, Girish S, Li C. Population pharmacokinetics (PK) and exposure-response (E-R) analysis of trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (MBC) who have received at least two prior regimens of HER2-directed therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-26.

CPT: Pharmacometrics & Systems Pharmacology, 2021

Journal of Crohn's & colitis, Jan 17, 2017

A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in ... more A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis (UC) or Crohn's disease (CD) has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 (Caverage) as exposure measure. Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship; more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10%...

Wiley StatsRef: Statistics Reference Online, 2014

Alzheimer's & Dementia, 2010

Background: Various authors have evaluated disease progression in Alzheimer's disease (AD), using... more Background: Various authors have evaluated disease progression in Alzheimer's disease (AD), using patient data from individual clinical studies or pooled data across various trials. We conducted a systematic review of public data sources from 1990 to 2008 for all available AChE inhibitor studies, as well as clinical studies that evaluated the rate of deterioration in AD patients. Unique to this analysis, we developed a model based on literature data to describe the longitudinal response in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) (change from baseline) in mild to moderate severity AD patients. The model was used to estimate disease progression for both placebo-treated patients and acetylcholinesterase (AChE)-inhibitor treated patients, and factors that affected disease progression. Methods: We collected 576 mean ADAS-cog changes from baseline data points of 52 trials, representing data from approximately 19,972 patients and more than 84,000 individual observations. The model described the rate of disease progression, the evident placebo effect, and the symptomatic effect of AChE-inhibitors. Baseline ADAS-cog, Mini-Mental State Examination score, age, and year of publication were tested as covariates. Results: The disease progression in mild to moderate AD patients across all available and relevant literature sources was estimated as 5.5 points per year. An Emax-type model best described the symptomatic drug effect of AChE inhibitors. The rate of disease progression (underlying disease progression) was no different between placebo and AChE-inhibitors groups. Baseline ADAS-cog is a significant covariate in disease progression. Baseline age was also tested as a covariate in the rate of disease progression, but the model was unable to describe any effects of age, likely because of the narrow distribution of mean age (literature-level analysis). There was no significant impact of publication year in the model. Conclusions: Baseline ADAS-cog is a significant covariate affecting the rate of disease progression, and it describes or at least explains the different rates of deterioration evident in early or late stages of the disease. There was no significant impact of publication year in the model, suggesting that disease progression has not slowed in more recent trials.

Alzheimer's & Dementia, 2009

Antimicrobial Agents and Chemotherapy, 2016

ABSTRACTInhalational anthrax has high mortality even with antibiotic treatment, and antitoxins ar... more ABSTRACTInhalational anthrax has high mortality even with antibiotic treatment, and antitoxins are now recommended as an adjunct to standard antimicrobial regimens. The efficacy of obiltoxaximab, a monoclonal antibody against anthrax protective antigen (PA), was examined in multiple studies conducted in two animal models of inhalational anthrax. A single intravenous bolus of 1 to 32 mg/kg of body weight obiltoxaximab or placebo was administered to New Zealand White rabbits (two studies) and cynomolgus macaques (4 studies) at disease onset (significant body temperature increase or detection of serum PA) following lethal challenge with aerosolizedBacillus anthracisspores. The primary endpoint was survival. The relationship between efficacy and disease severity, defined by pretreatment bacteremia and toxemia levels, was explored. In rabbits, single doses of 1 to 16 mg/kg obiltoxaximab led to 17 to 93% survival. In two studies, survival following 16 mg/kg obiltoxaximab was 93% and 62% c...

Journal of Crohn's & colitis, Jan 29, 2018

Cancer chemotherapy and pharmacology, Jan 11, 2017

In the phase III EMILIA study, trastuzumab emtansine (T-DM1) significantly improved progression-f... more 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...

Arthritis research & therapy, Jan 15, 2015

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tof... more Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib modulates the signaling of cytokines that are integral to lymphocyte activation, proliferation, and function. Thus, tofacitinib therapy may result in suppression of multiple elements of the immune response. Serious infections have been reported in tofacitinib RA trials. However, limited head-to-head comparator data were available within the tofacitinib RA development program to directly compare rates of serious infections with tofacitinib relative to biologic agents, and specifically adalimumab (employed as an active control agent in two randomized controlled trials of tofacitinib). A systematic literature search of data from interventional randomized controlled trials and long-term extension studies with biologics in RA was carried out. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results of the review and meta...

Objectives: Association of Vitamin D3 (D3) and its metabolite (25OHD3) exposure with various dise... more Objectives: Association of Vitamin D3 (D3) and its metabolite (25OHD3) exposure with various diseases, including bone health, diabetes, and cancer, has become an active area of research[1]. Clinical studies investigating these relationships with D3 and 25OHD3 vary in dosing regimen, assays, demographics, and control of endogenous D3 production. This leads to uncertain and conflicting exposure-related associations with D3 and 25OHD3. To elucidate this parent-metabolite system, a population PK (PPK) model was developed to predict D3 and 25OHD3 from varied doses and administration routes. Sources of variability related to 25OHD3 baseline (BL), weight (WT), and assay type were explored. Methods: Public source PK data pertaining to D3 and 25OHD3 in healthy or osteoporotic populations, including 57 studies representing 5406 individuals (25 individual-level and 122 group-level units), were selected using specified search criteria in PUBMED. Data included IV, oral, single and multiple dose ...

Clinical Pharmacology & Therapeutics, 2006

BACKGROUND/AIMS: Drug-induced QT interval prolongation, which can lead to torsade de pointes, is ... more BACKGROUND/AIMS: Drug-induced QT interval prolongation, which can lead to torsade de pointes, is a concern in drug development. The present study evaluated the predictability of nonclinical assays (in vitro hERG and in vivo safety pharmacology studies) for drug-induced QT interval prolongation.