Papers by Julie Passarell
Blood, Nov 13, 2019
Introduction: Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor that ... more Introduction: Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor that has shown clinical activity in patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3 internal tandem duplications in the phase 3 QuANTUM-R trial (Cortes et al, Lancet Oncol 2019; NCT02039726). In this analysis, exposure-response relationships of select efficacy endpoints of quizartinib were evaluated. Methods: Analysis was conducted for the following 2 studies separately: phase 2 study APS2689-CL-2004 and phase 3 QuANTUM-R study. Phase 2 study APS2689-CL-2004 enrolled 76 patients who were randomized to receive quizartinib 30 or 60 mg once daily (26.5 and 53.0 mg free base, respectively). Dose escalation was allowed and no dose reduction for strong cytochrome P450 3A (CYP3A) inhibitors was made in this study. In QuANTUM-R, 245 patients were randomized to receive quizartinib. The quizartinib dosing regimen was 30 mg/day and then escalated to 60 mg/day after 2 weeks if QTcF was ≤ 450 ms. Patients receiving a concurrent strong CYP3A inhibitor initiated quizartinib at 20 mg/day, with an increase to 30 mg/day, because concomitant use of a strong CYP3A inhibitor approximately doubles quizartinib exposure. Efficacy endpoints included in the analysis were rate of composite complete remission (CRc; complete remission (CR) + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery), duration of CRc, and overall survival (OS). Exposure measures in individual patients, such as average daily area under the curve (AUC), maximum concentration, and trough concentration, were obtained from a population pharmacokinetic analysis of quizartinib plasma concentration data (Kang et al, EHA 2019) and then used for correlating with the efficacy endpoints. Logistic regression analysis was used for CRc rate, and time-to-event analysis was performed for the duration of CRc and OS. The effect of quizartinib exposure on the percentage of subjects achieving bone marrow (aspirate) blasts of < 5% in QuANTUM-R was also assessed. Results: Patients were divided into 4 quartile groups according to average daily quizartinib AUC for the investigation of exposure-response relationships for OS and the duration of CRc. The lowest exposure quartile group showed shorter OS than the higher 3 quartile groups. The overall median OS from the intent-to-treat (ITT) population was 6.2 months in the phase 3 study; the median OS in the lowest exposure quartile group (Q1) was 4.5 months, whereas the median OS in the highest exposure quartile group (Q4) was 9.6 months (Fig. 1). Analysis of OS for the phase 2b study APS2689-CL-2004 demonstrated a similar trend, in which the lower AUC quartile demonstrated decreased OS. The overall OS from the ITT population was 5.2 months in the phase 2 study, and the median OS in Q1 and Q4 was 4.6 and 6.9 months, respectively (Fig. 2). Consistent with analyses for OS, the duration of CRc showed a trend of shorter duration of response in the lower AUC quartiles in both studies. Additionally, the lower AUC quartile appeared to result in a smaller proportion of subjects who achieved blast reduction of < 5% (ie, 33.3% in Q1 vs 45.6% to 52.6% in Q2 to Q4). However, no apparent trend of exposure-response relationship was shown for CRc (P > .05 from logistic regression analysis). Conclusions: Exposure-response analysis suggests a consistent trend for reduced clinical benefit at lower quizartinib AUC quartiles across various efficacy endpoints (but not CRc) in both the phase 2 and phase 3 studies. Current analysis supports the recommended dosing regimen of 30-mg starting dose with escalation to 60 mg as the target clinical dose. Figure Disclosures Kang: Daiichi Sankyo: Employment. Passarell:Cognigen Corporation: Employment. Abutarif:Daiichi Sankyo: Employment, Equity Ownership. Mendell:Daiichi Sankyo, Inc.: Employment. Yin:Daiichi Sankyo: Employment.
Cancer Chemotherapy and Pharmacology, Feb 6, 2010
Purpose-The pharmacokinetic profiles of bendamustine and active metabolites were defined in patie... more Purpose-The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma (NHL), and supported understanding of exposure-response relationships for efficacy and safety. Methods-Bendamustine was administered as a 60-minute 120 mg/m 2 intravenous infusion on Days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. Results-Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t 1/2 (40 minutes) was considered the pharmacologically relevant (beta elimination) t 1/2 since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m 2 administration, except bendamustine C max was a significant (p-value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. Conclusions-The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t 1/2 and low concentrations of bendamustine observed by 12 hours after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C max increases.
The Journal of Clinical Pharmacology, Mar 12, 2018
Eslicarbazepine acetate (ESL) is a once‐daily oral antiepileptic drug (AED) indicated for partial... more Eslicarbazepine acetate (ESL) is a once‐daily oral antiepileptic drug (AED) indicated for partial‐onset seizures (POS). ESL pharmacokinetics (PK) and exposure–response analyses were supported by 2 phase 3 conversion to ESL (1200, 1600 mg) monotherapy studies. The PK model development included 10 phase 1–2 studies (ESL 600–1200 mg daily). Seizure diaries were completed daily; subjects exited if seizures worsened. Exposure–response models were developed for time to study exit, probability of seizure freedom, time to first occurrence of dizziness, headache, and nausea; serum sodium levels were explored. A 1‐compartment model with first‐order absorption/elimination described ESL PK. Clearance and distribution volume were significantly related to body weight and sex. Higher eslicarbazepine minimum concentration (Cmin) and use of 1 baseline AED were associated with significantly lower risk of study exit, whereas eslicarbazepine Cmin was a significant predictor of seizure freedom during the last 4 weeks of monotherapy. Eslicarbazepine exposure and the time to first occurrence of adverse events were not related. A shallow negative relationship described the relationship between change from baseline in serum sodium level and eslicarbazepine exposure. Eslicarbazepine apparent clearance and distribution volume estimates were similar to those reported for ESL adjunctive therapy. Dose adjustment based on body weight was not required. The time to study exit and probability of seizure freedom during the last 4 weeks of monotherapy were weakly related to eslicarbazepine exposure. Because the first occurrence of adverse events or hyponatremia were also not significantly related to eslicarbazepine exposure, dose adjustment using plasma eslicarbazepine concentrations is not supported.
Clinical pharmacology in drug development, Jan 3, 2022
The efficacy of the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin was establish... more The efficacy of the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin was established in combination with chemotherapy as frontline treatment for advanced classical Hodgkin lymphoma in the randomized phase III ECHELON-1 study. Population pharmacokinetic (PK) and exposure-response models were developed to quantify sources of PK variability and relationships between exposure and safety/efficacy endpoints in ECHELON-1. The influence of patient-specific factors on the PK of the ADC and the microtubule-disrupting payload monomethyl auristatin E (MMAE) was investigated; none of the significant covariates had a clinically relevant impact. Exposure-response analyses evaluated relationships between time-averaged AUC (ADC, MMAE) and efficacy endpoints (ADC) or safety parameters (ADC, MMAE). Exposure-efficacy analyses supported consistent treatment benefit with brentuximab vedotin across observed exposure ranges. Exposuresafety analyses supported the recommended brentuximab vedotin starting dose (1.2 mg/kg every 2 weeks), and effective management of peripheral neuropathy and neutropenia with dose modification/reduction and febrile neutropenia with granulocyte colony-stimulating factor primary prophylaxis.
Acta Neurologica Scandinavica, May 6, 2018
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-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
The Journal of Clinical Pharmacology, Oct 19, 2018
Nivolumab, a fully human immunoglobulin G4 monoclonal anti-programmed death-1 antibody, has demon... more Nivolumab, a fully human immunoglobulin G4 monoclonal anti-programmed death-1 antibody, has demonstrated clinical benefits in multiple tumors, including classical Hodgkin lymphoma. The aim of this study was to characterize the pharmacokinetics (PK) of nivolumab in patients with classical Hodgkin lymphoma using a population approach and to assess the exposure-response (E-R) relationship for safety, thereby supporting the dose recommendation in patients with classical Hodgkin lymphoma. Nivolumab PK and the effect of covariates were consistent with that observed in solid tumors, except that baseline clearance of nivolumab was lower in patients with classical Hodgkin lymphoma by 28%. The E-R analysis for safety, characterized by a Cox proportional hazards model, indicated that the resulting increased nivolumab exposure (average concentration after the first dose) was not a significant predictor of the risk of grade ࣙ3 drug-related adverse events. Given the acceptable safety profile and observed benefit (65% objective response rate) with the nivolumab 3 mg/kg every 2 week dosing regimen for classical Hodgkin lymphoma, together with the flat E-R safety relationship, nivolumab demonstrated a favorable benefit-risk profile across the range of exposures of 3 mg/kg every 2 weeks in patients with classical Hodgkin lymphoma. Additional model-based simulation suggested that a flat dose of 240 mg every 2 weeks was predicted to produce similar exposures to that of 3 mg/kg every 2 weeks. Therefore, nivolumab 240 mg every 2 weeks is the recommended dosing regimen in the classical Hodgkin lymphoma population.
The Journal of Clinical Pharmacology, Oct 19, 2018
Nivolumab, a fully human immunoglobulin G4 monoclonal anti-programmed death-1 antibody, has demon... more Nivolumab, a fully human immunoglobulin G4 monoclonal anti-programmed death-1 antibody, has demonstrated clinical benefits in multiple tumors, including classical Hodgkin lymphoma. The aim of this study was to characterize the pharmacokinetics (PK) of nivolumab in patients with classical Hodgkin lymphoma using a population approach and to assess the exposure-response (E-R) relationship for safety, thereby supporting the dose recommendation in patients with classical Hodgkin lymphoma. Nivolumab PK and the effect of covariates were consistent with that observed in solid tumors, except that baseline clearance of nivolumab was lower in patients with classical Hodgkin lymphoma by 28%. The E-R analysis for safety, characterized by a Cox proportional hazards model, indicated that the resulting increased nivolumab exposure (average concentration after the first dose) was not a significant predictor of the risk of grade ࣙ3 drug-related adverse events. Given the acceptable safety profile and observed benefit (65% objective response rate) with the nivolumab 3 mg/kg every 2 week dosing regimen for classical Hodgkin lymphoma, together with the flat E-R safety relationship, nivolumab demonstrated a favorable benefit-risk profile across the range of exposures of 3 mg/kg every 2 weeks in patients with classical Hodgkin lymphoma. Additional model-based simulation suggested that a flat dose of 240 mg every 2 weeks was predicted to produce similar exposures to that of 3 mg/kg every 2 weeks. Therefore, nivolumab 240 mg every 2 weeks is the recommended dosing regimen in the classical Hodgkin lymphoma population.
Diagnostic Microbiology and Infectious Disease, Feb 1, 2009
Correctly determined susceptibility breakpoints are important to both the individual patient and ... more Correctly determined susceptibility breakpoints are important to both the individual patient and to society at large. A previously derived patient population pharmacokinetic model and Monte Carlo simulation (9999 patients) were used to create a likelihood distribution of tigecycline exposure, as measured by the area under the concentration-time curve at 24 h (AUC 24). Each resultant AUC 24 value was paired with a clinically relevant fixed MIC value ranging from 0.12 to 2 mg/L. For each AUC 24-MIC pair, the probability of microbiologic response was calculated using an exposure-response relationship, which was derived from patients with complicated skin and skin structure infections that involved Staphylococcus aureus or streptococci or both. The median probability of microbiologic success was 94% or greater for MIC values up to and including 0.25 mg/L. The median probability of microbiologic success was 66% or less for MIC values of 0.5 mg/L or greater. These data support a susceptibility breakpoint of 0.25 mg/L for S. aureus and streptococci.
Clinical Drug Investigation, Nov 23, 2015
Background and Objectives Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptak... more Background and Objectives Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of attentiondeficit/hyperactivity disorder (ADHD). Uniquely, relative to current ADHD medications, dasotraline has a slow absorption and long elimination half-life. Here we relate the pharmacokinetics and pharmacodynamics of dasotraline to reduction in ADHD symptoms based on simulated clinical trial outcomes. Methods Dasotraline pharmacokinetics were analyzed by population pharmacokinetic methodologies using data collected from 395 subjects after single or multiple oral dose administrations ranging from 0.2 to 36 mg (three phase I studies and one phase II ADHD study). Population pharmacokinetic and pharmacodynamic models related individual dasotraline exposures to norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations, ADHD symptoms, and study discontinuation (probability of dropout). Results Dasotraline pharmacokinetics were described by a one-compartment model with dual (linear plus nonlinear) elimination. In an ADHD population treated with dasotraline 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 h and plasma concentrations reached steady-state by 10 days of dosing. A population pharmacokinetic and pharmacodynamic model of DHPG indicated clinically significant norepinephrine transporter inhibition was achieved as a function of time-matched dasotraline concentrations. Dasotraline exposure reduced ADHD symptoms in a sigmoid E max time-course model. Clinical trial simulations described the effects of dose, duration, and sample size on clinical outcomes. Conclusion These results related dasotraline pharmacokinetics to pharmacological activity in ADHD, and support the novel concept that maintaining constant, steady-state dopamine and norepinephrine reuptake inhibition throughout a 24-h dosing interval is a novel pharmacological approach to the management of ADHD symptoms. Clinicaltrials.gov identifier: NCT01692782.
medRxiv (Cold Spring Harbor Laboratory), Nov 27, 2022
are employees of Vir Biotechnology and report stock ownership in Vir Biotechnology and third-part... more are employees of Vir Biotechnology and report stock ownership in Vir Biotechnology and third-party funding from GSK to Vir Biotechnology All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
Antimicrobial Agents and Chemotherapy, May 17, 2022
An exposure–efficacy analysis of the phase 3 ASPECT-NP trial was performed to evaluate the relati... more An exposure–efficacy analysis of the phase 3 ASPECT-NP trial was performed to evaluate the relationship between plasma exposure of ceftolozane and tazobactam and efficacy endpoints (primary: 28-day all-cause mortality; key secondary: clinical cure at test-of-cure visit) in adult participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP). Participants ( N = 231) from the ceftolozane/tazobactam treatment group in the intention-to-treat population who had pharmacokinetic data available and relevant baseline lower respiratory tract (LRT) pathogen(s) susceptibility data were included.
Clinical Cancer Research, Jan 3, 2022
Purpose: A benefit:risk assessment for a less-frequent nivolumab 480 mg every 4 weeks + cabozanti... more Purpose: A benefit:risk assessment for a less-frequent nivolumab 480 mg every 4 weeks + cabozantinib 40 mg every day dosing regimen was predicted using modeling and simulation of clinical trial data from nivolumab monotherapy studies and from the nivolumab 240 mg every 2 weeks + cabozantinib 40 mg every day dosing regimen, which demonstrated clinical benefit versus sunitinib in previously untreated advanced renal cell carcinoma (aRCC) in the phase III CheckMate 9ER trial (NCT03141177). Patients and Methods: Multivariable Cox proportional hazards analyses were conducted using nivolumab monotherapy data in previously treated aRCC and data from CheckMate 9ER to evaluate progression-free survival (PFS), overall survival (OS), and grade ≥2 immune-mediated adverse events (IMAE). Results: Nivolumab 240 mg every 2 weeks + cabozantinib versus nivolumab monotherapy showed improvement in PFS (HR, 0.38; 95% CI, 0.31–0.47), OS (HR, 0.63; 95% CI, 0.46–0.85), and increased risk of grade ≥2 IMAEs (HR, 2.19; 95% CI, 1.79–2.67). Nivolumab exposure was not a predictor of PFS/OS or grade ≥2 IMAEs. Lower nivolumab clearance, male sex, higher baseline bodyweight, and Karnofsky performance (100) were each associated with PFS/OS improvements. Region and International Metastatic Renal Cell Carcinoma Database Consortium poor score were negative OS predictors. Age, baseline albumin, and programmed death ligand 1 status were not significant PFS/OS predictors. Cabozantinib was a significant grade ≥2 IMAE predictor, driven by diarrhea and hepatic events. Model-predicted PFS/OS and grade ≥2 IMAE rates were similar (<2.5% difference) for nivolumab 240 mg every 2 weeks + cabozantinib and 480 mg every 4 weeks + cabozantinib. Conclusions: Comparable benefit:risk was predicted for nivolumab 480 mg every 4 weeks + cabozantinib and nivolumab 240 mg every 2 weeks + cabozantinib.
Clinical pharmacology in drug development, Mar 19, 2021
Galcanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, was rece... more Galcanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, was recently approved for migraine prophylaxis. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between galcanezumab concentration and inhibition of capsaicin-induced dermal blood flow (CIDBF) was evaluated using first-inhuman data following 6 single subcutaneous dose levels (1 to 600 mg) or multiple (4) 150 mg doses q2wk in 7 cohorts (n = 7 active/2 placebo-treated healthy subjects). Galcanezumab pharmacokinetics were best described by a 1compartment model with delayed first-order absorption/linear elimination. Apparent estimates (between-subject variability) of clearance, volume of distribution, absorption rate constant, and lag time were 0.0106 L/h (27 %CV), 11.2 L (21 %CV), 0.0192 1/h (89 %CV), and 0.202 h, respectively. Estimated elimination half-life was about 30 days. An effect compartment link model described the concentration-effect relationship; estimated maximum inhibitory effect was 70.5% and 50% maximum inhibitory effect concentration (IC50) was 1060 ng/mL. Galcanezumab showed dose-and concentration-dependent potent and durable inhibition of CIDBF. Simulated effect compartment concentrations were maintained above IC50 after 12 weeks of dosing. Near maximal CIDBF inhibition occurred with 150 mg biweekly for 12 weeks, lasting ≥ 24 weeks or with ≥ 30 mg q2wk or 195 mg q13wk. Quantitative modeling of galcanezumab PK/PD supported dose selection for the phase 2 proof-of-concept study.
Clinical and Translational Science, Dec 27, 2019
Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudina... more Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudinal exposureresponse relationships for total cariprazine (sum of cariprazine and its major active metabolites) in 2,558 patients with schizophrenia or bipolar mania. Drug exposure metrics were explored for potential relationships with efficacy and safety end points. Total cariprazine exposures were significantly related to reductions in Positive and Negative Syndrome Scale (PANSS) or Young Mania Rating Scale (YMRS) total scores in schizophrenia or bipolar mania, respectively, via a maximum effect (E max)-type relationship. Typical steady-state plasma concentrations after 3 and 4.5 mg/day were associated with 50% of maximum typical reductions in PANSS and YMRS total scores, respectively. Time-weighted cariprazine exposures had significant relationships with the probability of common adverse events (AEs). Dose increase was associated with increased efficacy but was also associated with an increase in AEs. Results of these pharmacokinetic/pharmacodynamic analyses support that the recommended dose range (1.5-6 mg/day for schizophrenia and 3-6 mg/day for bipolar mania) provides an appropriate benefit-risk balance between cariprazine efficacy and safety. Identifying the appropriate efficacious dose for an antipsychotic is often confounded by placebo response and high dropout rate in psychiatric clinical trials. 1,2 Population pharmacokinetic/pharmacodynamic (PK/PD) modeling, in which data from several studies can be analyzed simultaneously, 3 is a useful tool for clarifying exposure-response relationships and can assess the cumulative data to support optimal clinical dose. Model-based analysis also increases the power to detect differences in clinical trials. 4 Cariprazine is an orally active and potent dopamine D 3-preferring D 3 /D 2 receptor partial agonist and a serotonin 5-HT 1A receptor partial agonist. 5 Cariprazine also acts as an antagonist at 5-HT 2B receptors, with lower affinity for 5-HT 2A , 5-HT 2C , histamine H 1 , and adrenergic α 1 receptors and negligible affinity for other receptors (e.g., cholinergic muscarinic receptors). 5 Two major metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine
Antimicrobial Agents and Chemotherapy, 2008
Exposure-response analyses were performed to test the microbiological and clinical efficacies of ... more Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono-or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/ MIC ratio was also borderline predictive of microbiological response (P ؍ 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.
Cancer Chemotherapy and Pharmacology, Oct 9, 2007
Reversible transient elevations in transaminases have been observed after trabectedin administrat... more Reversible transient elevations in transaminases have been observed after trabectedin administration. A semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed to evaluate the time course of alanine aminotransferase (ALT) elevation, tolerance development, and the hepatoprotective effect of dexamethasone on trabectedin-induced transient transaminitis following different dosing schedules in cancer patients. Trabectedin was administered to 711 patients as monotherapy (dose range: 0.024-1.8 mg/m(2)) as 1-, 3-, or 24-h infusions every 21 days; 1- or 3-h infusions on days 1, 8, and 15 every 28 days; or 1-h infusions daily for five consecutive days every 21 days. Population PKPD modeling was performed with covariate evaluation [dexamethasone use (469/711 pt), ECOG performance status scores (89.7% pts <or= 1), and body weight (36-122 kg)] on PD parameters, followed by model validation. Simulations assessed the influence of dosing regimen and selected patient factors on the time course of ALT and the effectiveness of the dose reduction strategy. A precursor-dependent PKPD model described the temporal relationship between ALT elevation and trabectedin concentrations, where the transfer process of ALT from hepatocytes to plasma is stimulated by trabectedin plasma concentrations. Overall, 66% of patients had transaminitis. Mean predicted (%SEM) baseline ALT (ALT(o)) and t (1/2) in plasma were 31.5 (5.1) IU/L and 1.5 days, respectively. The magnitude of the trabectedin stimulation of the ALT transfer rate from hepatocytes to plasma was 11.4% per 100 pg/mL of trabectedin plasma concentration. Dexamethasone decreased the rate of trabectedin-induced ALT release from hepatocyte by 63% (P < 0.001). Model evaluation showed that the model predicted incidence of grade 3/4 transaminase elevation was similar to the observed values. Simulations showed that severity of ALT elevation was dose- and schedule-dependent. The dose reduction strategy decreased the incidence of grade >or=3 toxicity by 13 and 39% following two and four cycles of therapy, respectively. A PKPD model quantifying the hepatoprotective effect of dexamethasone on transient and reversible transaminitis following trabectedin treatment has been developed. The model predicts that co-administration of dexamethasone and the suggested dose reduction strategy based on the serum concentration of liver enzymes will enhance the safe use of trabectedin in the clinic.
Antimicrobial Agents and Chemotherapy, Jun 1, 2007
Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecy... more Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC 24)/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P ؍ 0.0001 for microbiological response and P ؍ 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P ؍ 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.
Antimicrobial Agents and Chemotherapy, Oct 1, 2001
Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory trac... more Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC 24)/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving Streptococcus pneumoniae. The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levofloxacin versus gatifloxacin for the treatment of community-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC 24 s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented S. pneumoniae infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classification and Regression Tree analysis. A statistically significant (P ؍ 0.013) relationship between microbiological response and the free-drug AUC 24 /MIC ratio was detected. At a free-drug AUC 24 /MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC 24 /MIC ratio of >33.7, it was 100% (P < 0.01). These findings may provide a minimum target free-drug AUC 24 /MIC ratio for the treatment of infections involving S. pneumoniae with fluoroquinolone antibiotics and provide a paradigm for the selection of fluoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. Further, when target free-drug AUC 24 /MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and S. pneumoniae.
Clinical pharmacology in drug development, Mar 7, 2023
Journal of Clinical Psychopharmacology, Oct 3, 2022
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