Evaluation of Methods for Estimating Time to Steady State with Examples from Phase 1 Studies

An overview is provided of the methodologies used in determining the time to steady state for Phase 1 multiple dose studies. These methods include NOSTASOT (no-statistical-significance-of-trend), Helmert contrasts, spline (quadratic) regression, effective half life for accumulation, nonlinear mixed effects modeling, and Bayesian approach using Markov Chain Monte Carlo (MCMC) methods. For each methodology we describe its advantages and disadvantages. The first two methods do not require any distributional assumptions for the pharmacokinetic (PK) parameters and are limited to average assessment of steady state. Also spline regression which provides both average and individual assessment of time to steady state does not require any distributional assumptions for the PK parameters. On the other hand, nonlinear mixed effects modeling and Bayesian hierarchical modeling which allow for the estimation of both population and subject-specific estimates of time to steady state do require distributional assumptions on PK parameters. The current investigation presents eight case studies for which the time to steady state was assessed using the above mentioned methodologies. The time to steady state estimates obtained from nonlinear mixed effects modeling, Bayesian hierarchal approach, effective half life, and spline regression were generally similar.     

A randomized, placebo-controlled study of the effects of telcagepant on exercise time in patients with stable angina

Telcagepant is a calcitonin gene-related peptide (CGRP) receptor antagonist being evaluated for acute migraine treatment. CGRP is a potent vasodilator that is elevated after myocardial infarction, and it delays ischemia during treadmill exercise. We tested the hypothesis that CGRP receptor antagonism does not reduce treadmill exercise time (TET). The effects of supratherapeutic doses of telcagepant on TET were assessed in a double-blind, randomized, placebo-controlled, two-period, crossover study in patients with stable angina and reproducible exercise-induced angina. Patients received telcagepant (600 mg, n = 46; and 900 mg, n = 14) or placebo and performed treadmill exercise at T(max) (2.5 h after the dose). The hypothesis that telcagepant does not reduce TET was supported if the lower bound of the two-sided 90% confidence interval (CI) for the mean treatment difference (telcagepant-placebo) in TET was more than -60 s. There were no significant between-treatment differences in TET (mean treatment difference: -6.90 (90% CI: -17.66, 3.86) seconds), maximum exercise heart rate, or time to 1-mm ST-segment depression using pooled data or with stratification for dose.     

Activity and safety of dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab in very elderly patients with poor-prognostic untreated diffuse large B-cell non-Hodgkin lymphoma

BACKGROUND: This study was designed to assess the activity and safety of dose‐adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab (DA‐POCH‐R) in elderly patients with poor‐prognostic untreated diffuse large B‐cell non‐Hodgkin lymphoma (DLBCL). METHODS: From April 2006 to November 2009, 23 patients, aged ≥70 years, with an age‐adjusted International Prognostic Index (IPI) of 2 or 3, were enrolled. Only patients with left ventricular ejection fraction (LVEF) ≥50% were allowed. The DA‐POCH‐R regimen was administered every 3 weeks for a minimum of 6 and a maximum of 8 cycles. RESULTS: Median patient age was 77 years (range, 70‐90 years); 83% of patients had Ann Arbor stage III to IV disease. Median LVEF at baseline was 62%. Four (17%) patients had a history of abnormal cardiovascular conditions. Twenty‐one (91%) patients were evaluable for response. The overall response rate was 90%, with a complete response rate of 57%. The 3‐year overall survival and event‐free survival rates were 56% and 54%, respectively. Neutropenia (48%) was the most frequent grade 3 to 4 adverse event (AE); no grade 3 to 4 cardiac AEs were observed. CONCLUSIONS: DA‐POCH‐R was an active and safe combination therapy for patients aged ≥70 years with poor‐prognostic untreated DLBCL. This regimen was a reasonable alternative for elderly patients who were not considered to tolerate standard R‐CHOP treatment. Cancer 2011. © 2010 American Cancer Society.     

Double-blind crossover study to assess potential differences in cytochrome P450 3A4 activity in healthy subjects receiving ondansetron plus dexamethasone, with and without aprepitant

Purpose

Because glucocorticoids and the neurokinin-1 receptor antagonist aprepitant influence CYP3A4 activity, this study assessed whether aprepitant added to a 5-HT₃ antagonist and glucocorticoid would affect CYP3A4 induction.

Methods

In this double-blind, 2-period crossover study, 12 subjects were randomized to receive a triple regimen (oral aprepitant [A] 125?mg, intravenous ondansetron [O] 32?mg, and oral dexamethasone [D] 12?mg?day 1; A 80?mg and D 8?mg?days 2?C3; D 8?mg?day 4) in 1 of 2 periods, and a dual regimen (O 32?mg and D 20?mg?day 1; D 8?mg bid days 2?C4); the D dose was adjusted to account for known dexamethasone/aprepitant interaction. Oral (2?mg) and intravenous (1?mg) stable isotope (¹³C₅ ¹⁵N₁)?Clabeled midazolam were simultaneously given as probes on days ?1, 6, 8, 15, and 22 of each period. If the a priori 90% confidence interval for the day 6 geometric mean oral midazolam AUC_0?C?? ratio (triple/dual regimen) of fold-change from baseline was above 0.5, it would be concluded that there was no clinically meaningful between-regimen difference in CYP3A4 activity.

Results

Day 6 oral midazolam AUC_0?C?? geometric mean fold-change from baseline was 0.84 (0.30?C1.58 with A, 0.46?C1.69 without A). The ratio of geometric mean oral midazolam AUC_0?C?? fold-changes was 1.00 (90% confidence interval 0.80, 1.25).

Conclusions

Aprepitant plus a 5-HT₃ antagonist and dexamethasone is unlikely to have a significant additional inductive effect on CYP3A4 activity beyond that of the dual regimen.     

Complete response to the combination therapy with androgen blockade and somatostatin analogue in a patient with advanced prostate cancer: magnetic resonance imaging with 1H-spectroscopy

A 74-yr-old man with prostatic adenocarcinoma underwent magnetic resonance 1H-spectroscopic imaging (1H-MRSI) of the prostate. Based on the results, he was treated with combination therapy using complete androgen blockade (leuprorelin acetate 3.75 mg every 4 wk plus bicalutamide 50 mg daily) and a somatostatin analogue (lanreotide acetate 60 mg every 4 wk). Serum prostate-specific antigen and chromogranin A levels steadily decreased over a 12-mo follow-up period, at which time the patient is alive without disease progression and with a complete objective and symptomatic response.     

The use of bisphosphonates in palliative treatment of bone metastases in a terminally ill, oncological elderly population

According to the guidelines of WHO [WHO, 1999. Cancer Pain and Palliative Care Program. Cancer Pain Release, vol. 13], the term terminally ill patient refers to oncological patients whose life expectancy is lower than 90 days, and the index of their physical state (defined as the Karnofsky Index) is below 50. The terminally ill oncological patients are treatable with the palliative cures, representing a treatment system aimed at improving the quality of life (QOL) of both the patient and the family members, decreasing the physical and psychical sufferance of the patient. The present study followed 35 terminally ill oncological patients with bone metastases, at their homes, for the University of Catania. These patients had previously been followed by the Local Sanitary Unit (ASL 3) of Catania, and established a life expectancy not longer than 3 months. Independently from the basic neoplastic disease resulting in the bone metastases, all the patients were treated with sodium clodronate (SC) intravenously, 300 mg every second day, in order to decrease the bone pains. The visual analogue scale (VAS) for pain relief, the autonomy (IADL) and autosufficiency (ADL, Barthel Index) were evaluated after 1, 3, and 6 months of treatment. The results indicate an overall significant improvement both in the pain symptoms and the QOL. Also the compromised autonomy and autosufficiency of this population seemed to be improved, at least as compared to the predicted and expected results at the start of this trial, and also compared to the relevant literature. One can conclude that the i.v. application of 300 mg of SC every other day produced a significant pain reduction and improved the QOL, and helped in maintaining the actual autonomy and autosufficiency. On this basis we suggest the use of this compound in the given type of terminally ill patients.     

Safety,tolerability, and pharmacokinetics of single‐ and multiple‐dose administration of islatravir (MK‐8591) in adults without HIV

Islatravir (MK‐8591) is a nucleoside analogue in development for the treatment and prevention of HIV‐1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18–60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir‐triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high‐fat meal. In Study 2, 8 participants per dose received 3 once‐weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well‐tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half‐life was 49–61 h; intracellular islatravir‐triphosphate half‐life was 118–171 h. Plasma exposure increased in an approximately dose‐proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir‐triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir‐triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

​Current HIV treatment and prevention strategies have limitations, and novel agents that offer improved safety and tolerability, a high barrier to HIV resistance, and more convenient dosing regimens are required.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Two phase 1 studies in participants without HIV assessed safety and pharmacokinetics of rising single and multiple doses of oral islatravir, a nucleoside analogue, to support continued development for the treatment and prevention of HIV‐1 infection.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Islatravir was generally well‐tolerated at single doses up to 400 mg. Oral doses of islatravir greater than or equal to 10 mg resulted in intracellular peripheral blood mononuclear cell levels of the active form, islatravir‐triphosphate, comparable to those associated with antiviral efficacy in preclinical studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These studies provide important safety and pharmacokinetic information about islatravir in adults without HIV, which will be used to support further clinical investigation of islatravir for the treatment and prevention of HIV‐1 infection.