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Clinical Pharmacology
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
William B. Abrams, Keith H. Jones
It is customary to conduct investigations over a dose range adequate to determine a pharmacological effect and its dose relationship, or to achieve a fixed multiple of the proposed therapeutic dose, or to define a maximum tolerated dose. Predetermination of these dosage limits and the intervals between dosing are important aspects of study design. During early studies, dosage increments are frequently a matter of doubling, though numerous possible increment alternatives exist according to the characteristics of the drug substance, the objectives of the study, or the availability of the volunteers. If a maximum tolerated dose is established, then further studies proceed at a fraction (maybe one-half to two-thirds) of that dose to establish repeated dose tolerability and safety. Alternatively, if blood drug concentrations have been measured, subsequent dosing procedures may be determined, as noted above, on a pharmacokinetic basis. Occasionally, early pharmacokinetic or metabolic studies using single low-dose, highspecific-activity, radiolabeled drug may prove useful in establishing a further program of evaluation. This is especially so if such data have been found useful during preclinical and animal assessment.
Human Bcl-2 Antisense Therapy for Lymphomas
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Finbarr E. Cotter, Andrew Webb, Paul Clarke, David Cunningham
The starting dose was 4.6 mg/m/day, which was equivalent to below the 1/10th LD10 in mice. The dose was increased by 100% within each patient cohort unless grade 2 or greater toxicity was observed, according to the EORTC schema (EORTC, 1994). The maximum tolerated dose was defined as the dose that causes grade 3 or 4 toxicity in 50% or more patients. Response was evaluated from CT scan performed pretreatment, at weeks 2 (end of infusion) and 6, and classified using the WHO criteria (Miller et al., 1981).
The need for liberal regulations for promoting evidence-based Ayurveda
Published in C. P. Khare, Evidence-based Ayurveda, 2019
Studies conducted in Phase I, usually intended to involve one or both of the following objectives: Maximum tolerated dose: To determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. These studies include both single and multiple dose administration.Early measurement of Drug activity: Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. Such studies are generally performed in later Phases but may be appropriate when the drug activity is readily measurable with a short duration of drug exposure in participants at this early stage.
A Chemically Defined TLR3 Agonist with Anticancer Activity
Published in OncoImmunology, 2023
Julie Le Naour, Sylvain Thierry, Sarah Adriana Scuderi, Mathilde Boucard-Jourdin, Peng Liu, Marc Bonnin, Yuhong Pan, Clémence Perret, Liwei Zhao, Misha Mao, Chloé Renoux, María Pérez-Lanzón, Baptiste Martin, Oliver Kepp, Guido Kroemer, Bettina Werlé
TL-532 was i.v. injected in cynomolgus monkeys (one group of one male and one female) on days 1, 7, 13 and 19 at ascending concentrations of 35, 70, 140 and 280 mg/kg (dose volume of 2 mL/kg into the cephalic vein). Apart from erythema at the injection site, there were no major signs of toxiciy apart from an increase in alanine aminotransferase and aspartate aminotransferase activity at day 20, for the male only. The potential toxicity of TL-532 was then evaluated in three groups of monkeys (one male and one female) following three repeated i.v. (days 1, 5 and 9) injections of 70, 140 and 280 mg/kg in a dose volume of 2 mL/kg. TL-532 administered at 70 mg/kg induced no signs of toxicity in the male and female cynomolgus monkeys. TL-532 administered three times i.v. at 280 mg/kg, 4 days apart, induced changes in hematology parameters and bilateral pyelonephritis in the male and female cynomolgus monkeys (determined on day 10). This dose level was considered to be above the maximum tolerated dose. When administered three times at 140 mg/kg, changes induced were limited to minor clinical signs in females (piloerection, abnormal appearance of fur and/or alopecia) after the last dosing associated with body weight losses (−8%) and changes in hematology parameters in both genders (increase in total circulating leukocytes neutrophils, decrease in red blood cell count, hemoglobin and hematocrit).
The emerging role of antibody-drug conjugates in urothelial carcinoma
Published in Expert Review of Anticancer Therapy, 2020
Michael Lattanzi, Jonathan E. Rosenberg
A phase I dose escalation study was also carried out with intravesical oportuzumab monatox in NMIBC [107]. A total of 64 patients with BCG-refractory (or BCG-ineligible) NMIBC grade 2 or 3 and stage Ta or T1 or patients with carcinoma in situ were enrolled. Treatment was well-tolerated, and the maximum tolerated dose was not reached. Encouragingly, 39% of patients achieved a complete response at twelve weeks by cystoscopy and cytology. To better characterize the efficacy of this agent, investigators carried out a two-cohort phase II study of oportuzumab monatox (OM) in BCG-refractory urothelial carcinoma in situ [108]. Cohort 1 received an induction of 6 weekly doses intravesical OM, while cohort 2 received a twelve-dose induction; all patients were eligible for up to three maintenance cycles. Toxicities were generally mild and related to direct irritation of the bladder. Of 45 evaluable patients, 20 (44%) achieved a complete response, which is noteworthy given the lack of effective cystectomy-sparing local therapies in the BCG-refractory setting and the potential for immune-mediated adverse events with systemic anti-PD-1 immunotherapy. Unfortunately, only 16% of responses were ongoing at last follow-up (18–25 months), with a median time to recurrence of 274 days and 408 days in cohorts 1 and 2, respectively. A phase I trial is underway investigating the safety of intravesical OM in combination with the systemic PD-L1 antibody durvalumab (NCT03258593).
Pertuzumab for the treatment of breast cancer
Published in Expert Review of Anticancer Therapy, 2020
Marie Robert, Jean-Sébastien Frenel, Emmanuelle Bourbouloux, Dominique Berton Rigaud, Anne Patsouris, Paule Augereau, Carole Gourmelon, Mario Campone
In a phase I study of pertuzumab of 21 patients with advanced solid tumours, pertuzumab was administered at increased doses (0.5–15mg/kg) every 3 weeks. Pertuzumab’s mean terminal half-life for 2 to 15mg/kg ranged from 14.9 to 22.3 days. This was consistent with other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen [17]. At doses from 2 to 15mg/kg, dosing did not modify the systemic clearance, the volume of distribution of the central compartment, the volume of distribution at steady-state, and the elimination half-life (Table 2). At the 0.5mg/kg dose, pertuzumab cleared faster compared to the 2 to 15mg/kg dose where serum concentrations decreased faster the first 2 to 3 days and more slowly thereafter. Similarly, a shorter mean elimination half time was observed: 2.6 ± 0.9 days. The maximum tolerated dose was not reached. The recommended regimen was defined as a fixed-dose of 420mg every 3 weeks with a loading dose of 840mg (equivalent dose of 6mg/kg for a 70kg patient) [17]. In a pharmacokinetic study of 421 patients, although body weight and BSA were significant covariates affecting clearance and distribution volume, they only explained a small percentage of interpatient variability [24]. This supported the use of a flat dose of pertuzumab for all patients.