A Modified Delphi Study to Establish Essential Clinical Pharmacology Competencies.

INTRODUCTION: Competency-based education has been commonly used to enhance the healthcare workforce for some time. A translational discipline that is integral to drug development and impactful on healthcare and public health is clinical pharmacology. With such contribution, it is essential that the clinical pharmacology workforce is adequately equipped to address the demands of emerging trends of drug development. OBJECTIVES: The primary objective of this study was to determine the most significant competencies needed for a clinical pharmacologist in the regulatory environment. METHODS: A two round modified Delphi technique was administered to 29 clinical pharmacologists within the Office of Clinical Pharmacology (OCP) between November 2021-January 2022. A questionnaire consisting of core and technical competencies was administered electronically using SurveyMonkey ® to gain consensus about essential clinical pharmacology competencies. Participants used a Likert scale to rank importance of competencies from strongly agree (1), agree (2), neutral (3), disagree (4), strongly disagree (5). Participants also suggested topics to be included in the next round. Consensus was set at 60%. The competencies receiving the most consensus at 60% in round one and the new topics proceeded to the second round. In the second and final round, participants ranked the suggested competencies. Descriptive statistics and a McNemar change test were utilized to analyze data. Only data from the participants who completed both rounds was used in the study. RESULTS: In round one participants ranked all fifty-six core and technical competencies as essential with consensus of at least 60%. In round two, participants ranked sixty-two competencies as essential with consensus of at least 60%. A McNemar change test demonstrated stability of ranking between rounds. CONCLUSION: Essential core and technical competencies can build education programs to sustain the emerging clinical pharmacology workforce in the Office of Clinical Pharmacology. The Delphi technique is a suitable approach to determine essential competencies because it cultivates consensus and gains insight from experts in the forefront of drug development.

Urine Osmolality Is a Potential Marker of Longer-term Efficacy of Tolvaptan in ADPKD: A Post-hoc Analysis.

BACKGROUND: Total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) are measures of progression and treatment response in autosomal dominant polycystic kidney disease (ADPKD), but utility is limited by the long follow-up required for change assessment. In an analysis of data from the 3-year TEMPO 3:4 trial, we evaluated relationships among a short-term indicator of drug activity (change in urine osmolality [Uosm]) and longer-term outcomes to evaluate Uosm as a potential marker of efficacy. METHODS: Linear regression modeling and single-point analyses assessed relationships among change in Uosm to week 3, change in TKV to month 12, and change in eGFR to month 36 in subjects treated with tolvaptan (n=961) or placebo (n=483). Multivariate models evaluated the proportion of the tolvaptan treatment effect on eGFR attributable to change in Uosm. RESULTS: Change in TKV to month 12 and Uosm to week 3 each correlated with change in eGFR to month 36, regardless of treatment assignment. A greater decrease in Uosm from baseline to week 3 was indicative of a slower decrease in eGFR to month 36 (slope estimate of -0.01, P <0.00001). The effect of tolvaptan on Uosm accounted for 68.8% of the treatment effect on change in eGFR to month 36. Simulations of TEMPO 3:4 under the null hypothesis (i.e., replacement of all values for change in Uosm from baseline to week 3 with values from the placebo arm only) yielded a Type 1 error rate indicating an acceptable risk of falsely concluding treatment efficacy based on change in Uosm as a trial endpoint. CONCLUSIONS: Change in Uosm is a potential biomarker for long-term treatment outcome with tolvaptan and might expedite clinical trials and treatment decision-making for drugs with similar mechanisms of action.

Guiding Dyslipidemia Treatment: A Population Pharmacokinetic-Pharmacodynamic Framework for Obicetrapib.

Obicetrapib is a selective inhibitor of cholesteryl ester transfer protein that is currently in phase 3 of development for the treatment of dyslipidemia as adjunct therapy. The purpose of this study was to comprehensively characterize the pharmacokinetic (PK) and pharmacodynamic (PD) disposition of obicetrapib. Data from 7 clinical trials conducted in healthy adults and those with varying degrees of dyslipidemia were included for model development. The structural model that best described obicetrapib PK was a 3-compartment model with 4-compartment transit absorption and first-order elimination. Body weight was the only covariate found to significantly explain observed variability and was therefore included using allometric scaling on all disposition parameters. For a typical patient weighing 75 kg, the estimated apparent total body clearance and apparent volume of distribution of the central compartment was 0.81 L/h and 36.1 L, respectively. The final PK model parameters were estimated with good precision and were ultimately leveraged to sequentially inform 2 turnover models that describe obicetrapib's effect on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) concentrations. The maximum stimulatory effect of obicetrapib on LDL-C loss was estimated to be 1.046, while the maximum inhibitory effect of obicetrapib on HDL-C loss was 0.691. This corresponds to a predicted typical maximum percent change from baseline LDL-C and HDL-C of 51.1% and 224%, respectively. The final sequential model described obicetrapib PKPD well and was ultimately able to both demonstrate evidence of internal consistency and support decision-making throughout the development lifecycle.

A Model-Informed Drug Development Approach to Design a Phase 3 Trial of Teverelix Drug Product in Advanced Prostate Cancer Patients with Increased Cardiovascular Risk.

Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T < 0.5 ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360 mg SC and 180 mg IM with a maintenance dose of 360 mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.

Quantitation of Cabozantinib in Human Plasma by LC-MS/MS.

To support a phase III randomized trial of the multi-targeted tyrosine kinase inhibitor cabozantinib in neuroendocrine tumors, we developed a high-performance liquid chromatography mass spectrometry method to quantitate cabozantinib in 50 µL of human plasma. After acetonitrile protein precipitation, chromatographic separation was achieved with a Phenomenex synergy polar reverse phase (4 µm, 2 × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and 0.1% formic acid in water over a 5-min run time. Detection was performed on a Quattromicro quadrupole mass spectrometer with electrospray, positive-mode ionization. The assay was linear over the concentration range 50-5000 ng/mL and proved to be accurate (103.4-105.4%) and precise (<5.0%CV). Hemolysis (10% RBC) and use of heparin as anticoagulant did not impact quantitation. Recovery from plasma varied between 103.0-107.7% and matrix effect was -47.5 to -41.3%. Plasma freeze-thaw stability (97.7-104.9%), stability for 3 months at -80°C (103.4-111.4%), and stability for 4 h at room temperature (100.1-104.9%) were all acceptable. Incurred sample reanalysis of (N = 64) passed: 100% samples within 20% difference, -0.7% median difference and 1.1% median absolute difference. External validation showed a bias of less than 1.1%. This assay will help further define the clinical pharmacokinetics of cabozantinib.

A Phase 1 Randomized Dose-Escalation Study of a Human Monoclonal Antibody to IL-6 in CKD.

Background: Chronic systemic inflammation is highly prevalent in patients with CKD (measured as an elevated high-sensitivity C-reactive protein, hsCRP) and independently associated with cardiovascular events and all-cause mortality. An IL-6 blocker to suppress inflammation represents a potential novel paradigm to reduce cardiovascular risk in CKD. Methods: A phase 1 trial of ziltivekimab, a fully human mAb against IL-6, was conducted in patients with moderate-to-severe nondialysis-dependent CKD (eGFR of 20-60 ml/min per 1.73 m2) and evidence of chronic inflammation (hsCRP level >2 mg/L over two consecutive measurements). Three cohorts of n=4 (3:1 active:placebo) were blindly randomized to a single dose of ziltivekimab (5 mg, 15 mg, and 50 mg subcutaneous injection), and followed for 12 weeks for safety and pharmacokinetic/pharmacodynamic assessments, with an additional 20 weeks for safety and antidrug antibody assessments. Results: Participants were 67±11 years old; baseline eGFR: 40±13 ml/min per 1.73 m2; baseline hsCRP: 5.0±2.5 mg/L. Dose escalation was approved, and all adverse events were within the expected range for a CKD population with chronic inflammation. No serious adverse events were reported in any active cohort. hsCRP levels were substantially reduced with ziltivekimab. Of participants, 100% achieved suppression of hsCRP to <2 mg/L with the 15 mg and 50 mg dose, and several patients had undetectable levels of hsCRP with the 50 mg dose. The mean t1/2 ranged from of 45 to 65 days. Conclusions: In adults with moderate-to-severe CKD and evidence of chronic inflammation, a single-injection of the IL-6 inhibitor ziltivekimab was safe and highly effective at suppressing hsCRP over 12 weeks.

Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate.

PURPOSE: On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval. EXPERIMENTAL DESIGN: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response. RESULTS: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. CONCLUSIONS: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses.

Comparative evaluation of pharmacokinetics and pharmacodynamics of insulin glargine (Glaritus®) and Lantus® in healthy subjects: a double-blind, randomized clamp study.

AIMS: The objective of the study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of an insulin glargine formulation, Glaritus® (test) with the innovator's formulation Lantus® (reference) using the euglycemic clamp technique in a single-dose, double-blind, randomized, two sequences, four-period replicate crossover study in healthy volunteers (n = 40). METHODS: Subjects received subcutaneous administration of the insulin glargine (0.4 IU/kg) formulation at two occasions for test and reference and a 20% glucose solution was infused at variable rate to maintain euglycemia for 24 h. RESULTS: Both PK [area under the plasma concentration time curve (AUC0-24 h) and maximum insulin concentration (Cmax)] and PD endpoints [area under glucose infusion rate time curve (AUCGIR0-24) and maximum glucose infusion rate (GIRmax)] demonstrated bioequivalence of Glaritus to Lantus with the 90% confidence interval of geometric mean ratio of test to reference entirely contained within 0.80-1.25. Both formulations showed equivalent geometric least-square mean LSM value (0.08 nmol/L) for Cmax. The geometric LSM AUC0-24 h value for Glaritus® (1.09 h nmol/L) was comparable to Lantus (1.05 h nmol/L). Median Tmax values were also identical (12 h for both), and median t1/2 values were also equal (18 h for both). For GIRTmax, the difference between the means for the two was not statistically significant. No AEs related to study formulations were reported, and both products were well tolerated. CONCLUSIONS: The test product (Glaritus) was found to be bioequivalent to the reference product (Lantus). CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2015/06/005890; http://www.ctri.nic.in/ .

Exposure-Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients.

Purpose: To elucidate any differences in the exposure-response of alvocidib (flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure.Experimental Design: Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure-response relationships using unbound flavopiridol AUC were explored using recursive partitioning.Results: Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3).Conclusions: Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m2/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2/day) to achieve the higher exposures required for maximal efficacy in this population. Clin Cancer Res; 23(14); 3592-600. ©2017 AACR.

Levonorgestrel release rates over 5 years with the Liletta® 52-mg intrauterine system.

OBJECTIVE: To understand the potential duration of action for Liletta®, we conducted this study to estimate levonorgestrel (LNG) release rates over approximately 5½years of product use. METHODS: Clinical sites in the U.S. Phase 3 study of Liletta collected the LNG intrauterine systems (IUSs) from women who discontinued the study. We randomly selected samples within 90-day intervals after discontinuation of IUS use through 900days (approximately 2.5years) and 180-day intervals for the remaining duration through 5.4years (1980days) to evaluate residual LNG content. We also performed an initial LNG content analysis using 10 randomly selected samples from a single lot. We calculated the average ex vivo release rate using the residual LNG content over the duration of the analysis. RESULTS: We analyzed 64 samples within 90-day intervals (range 6-10 samples per interval) through 900days and 36 samples within 180-day intervals (6 samples per interval) for the remaining duration. The initial content analysis averaged 52.0±1.8mg. We calculated an average initial release rate of 19.5mcg/day that decreased to 17.0, 14.8, 12.9, 11.3 and 9.8mcg/day after 1, 2, 3, 4 and 5years, respectively. The 5-year average release rate is 14.7mcg/day. CONCLUSION: The estimated initial LNG release rate and gradual decay of the estimated release rate are consistent with the target design and function of the product. The calculated LNG content and release rate curves support the continued evaluation of Liletta as a contraceptive for 5 or more years of use. IMPLICATIONS STATEMENT: Liletta LNG content and release rates are comparable to published data for another LNG 52-mg IUS. The release rate at 5years is more than double the published release rate at 3years with an LNG 13.5-mg IUS, suggesting continued efficacy of Liletta beyond 5years.

Approval summary: imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase.

PURPOSE: The purpose is to describe the Food and Drug Administration (FDA) review and approval of imatinib (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in chronic phase. EXPERIMENTAL DESIGN: The FDA reviewed data in electronic format from a randomized controlled clinical trial of 1106 adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase, comparing imatinib with the combination of IFN-alpha and cytarabine. RESULTS: Imatinib showed clinically and statistically significantly better results for time-to-progression to accelerated phase or blast crisis, progression-free survival, complete hematological response rate, and cytogenetic response rate. With a median follow-up of 14 months, a maximum follow-up of 19.5 months, and an expected median survival of 5-6 years on the IFN-alpha/cytarabine control arm, few of the expected progressions to accelerated or blast phase or deaths have occurred. Imatinib was also better tolerated. Edema, nausea, rigors, neutropenia, and headache were more frequent in women. Only 57% of the IFN-alpha target dose was administered, and only 68% of patients received any cytarabine. However, this does not appear to adequately explain the superiority of imatinib observed in this trial. Results of a population pharmacokinetic study in a subgroup of 371 patients and a separate rifampin-imatinib drug-drug interaction study in healthy volunteers are presented. CONCLUSIONS: On December 20, 2002, imatinib was granted accelerated approval under subpart H, rather than regular approval. Follow-up is short compared with the natural history of chronic phase CML or more mature results with established therapies such as IFN-alpha or transplantation. If imatinib should stop working after 1.5-2 years, the results could be importantly different from the present analysis. As a Phase IV postmarketing commitment, the applicant has agreed to provide follow-up reports on this imatinib study annually for the next 6 years.

Clinical pharmacology review of escitalopram for the treatment of depression.

INTRODUCTION: Depression is a serious and debilitating psychiatric condition with serious societal health and economic implications. Escitalopram , the S-enantiomer of racemic citalopram, is an effective treatment for major depressive disorder. AREAS COVERED: This review covers the clinical pharmacology of escitalopram, with emphasis on regulatory approval. Its pharmacokinetics, pharmacodynamics and clinical efficacy for major depressive disorder are evaluated, along with data regarding safety and tolerability. EXPERT OPINION: Drug development of escitalopram was heavily guided by prior approval of citalopram. Select safety and efficacy studies for escitalopram in combination with supportive evidence from the results of prior citalopram studies allowed for regulatory approval for acute and maintenance claims in both adults and adolescents, while minimizing burden on the sponsor. Escitalopram has been shown to have better efficacy and safety profile than other selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor drugs, including racemic citalopram. The first generic escitalopram was approved in 2012, along with Abbreviated New Drug Applications. The associated cost savings have helped reduce the burden of weighing the benefits of escitalopram over less-expensive alternatives.

Knowledge management for efficient quantitative analyses during regulatory reviews.

Knowledge management comprises the strategies and methods employed to generate and leverage knowledge within an organization. This report outlines the activities within the Division of Pharmacometrics at the US FDA to effectively manage knowledge with the ultimate goal of improving drug development and advancing public health. The infrastructure required for pharmacometric knowledge management includes provisions for data standards, queryable databases, libraries of modeling tools, archiving of analysis results and reporting templates for effective communication. Two examples of knowledge management systems developed within the Division of Pharmacometrics are used to illustrate these principles. The benefits of sound knowledge management include increased productivity, allowing reviewers to focus on research questions spanning new drug applications, such as improved trial design and biomarker development. The future of knowledge management depends on the collaboration between the FDA and industry to implement data and model standards to enhance sharing and dissemination of knowledge.