Differences In Drug Tolerance Research Articles

Pirfenidone Therapy for Familial Pulmonary Fibrosis: A Real-Life Study

Familial pulmonary fibrosis (FPF) is defined as an idiopathic diffuse parenchymal lung disease affecting two or more members of the same primary biological family. The aim of this study was to compare disease progression and tolerance to pirfenidone in a population of FPF patients who presented with radiological and/or histological evidence of UIP, and a group of idiopathic pulmonary fibrosis (IPF) patients. Seventy-three patients (19 with FPF and 54 with IPF) were enrolled and data were collected retrospectively at 6, 12 and 24months follow-up. FPF patients were statistically younger and more frequently females. A significantly greater decline in FVC and DLCO was recorded in FPF than in IPF patients at 24months follow-up. At the 6-min walking test, walked distance declined significantly in FPF patients than IPF at 24months. No statistically significant differences in drug tolerance or side effects were recorded between groups. Different rate of progression was observed in patients with IPF and FPF on therapy with pirfenidone; our findings may not be due to lack of effectiveness of therapy, but to the different natural history and evolution of these two conditions. Pirfenidone was well tolerated by FPF and IPF patients. Specific unbiased randomized clinical trials on larger populations to validate our preliminary exploratory results are needed.

Chip-Based Genotyping: Translation of Pharmacogenetic Research to Clinical Practice

The observation of interindividual differences in drug tolerance is perhaps as old as pharmacotherapy itself. Since the 1950s several monogenetic traits have been described that explain differences in drug response or drug toxicity in population subsets (1). These early discoveries have evolved into our current understanding of pharmacogenetics as a complex trait. Therapy selection guided by gene test, however, has still not made the transition into clinical practice. In the current issue of Clinical Chemistry , Daly et al. (2) present a dedicated single-microarray assay, or gene chip, for comprehensive genotyping of potentially thousands of variants in genes involved in drug metabolism, excretion, and transport. These expanded capabilities are necessary because of the complexity of drug disposition. Single polymorphisms alone do not adequately predict drug disposition because multiple routes of metabolism or transport may compensate for deficiencies in a single pathway (3). For example, the anticancer drug irinotecan is not only metabolized by UGT1A1 but is also a substrate for transporter molecules coded by ABCB1 , ABCC2 , ABCG2 , and SLCO1B1 (4). Comprehensive genotyping based on gene chips allows large-scale studies on the utility of validated and exploratory biomarkers. The pharmacogenetic gene chip developed by Daly et al. (2) covers the 7 valid genomic biomarkers of drug disposition listed by the US Food and Drug …

Patient specific dosing in a cancer phase I clinical trial.

Recent improvements in our understanding of drug metabolism have led to the development of anticancer therapies that accommodate patient differences in drug tolerance. Such methods adjust the dose level according to measurable patient characteristics in order to obtain a target drug exposure. This paper describes the utilization of a patient specific dosing scheme in the statistical design of a phase I clinical trial involving patients with advanced adenocarcinomas of gastrointestinal origin. During the trial, dose levels were adjusted according to each patient's pretreatment concentration of an antibody that was shown in preclinical testing to moderate the effect of the agent under investigation. The design of the trial permitted a continual adjustment of the model used to tailor the dose to each patient's individual needs.

Phase I Study of Weekly Intravenous Infusions of CPT-11, a New Derivative of Camptothecin, in the Treatment of Advanced Non-Small-Cell Lung Cancer

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) is a novel camptothecin derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its unique inhibitory effects on mammalian DNA topoisomerase I. Seventeen patients with advanced non-small-cell lung cancer were treated with CPT-11 at weekly dose levels ranging from 50 to 150 mg/m2. At least three weekly doses were given to all patients except four, and a total of 74 weekly doses were given to the 17 patients. The dose-limiting toxic effects were myelosuppression (predominantly leukopenia) and unpredictable diarrhea. Gastrointestinal toxic effects were severe and not well controlled by standard therapy in some patients. Interpatient variability of toxic effects was substantial (including two deaths) and did not correlate with the pharmacokinetic parameters of CPT-11 and 7-ethyl-10-hydroxycamptothecin, its major metabolite. Two previously untreated patients, who received doses of 100 and 125 mg/m2, had partial responses lasting 3.2 and 4.0 months, respectively. The maximum tolerated dose on this schedule was 100 mg/m2, which we also recommend as a starting dose for phase II studies. This schedule appears to allow a CPT-11 dose intensity which is double the dose intensity possible on a once-a-month schedule. However, careful supervision to assess gastrointestinal toxic effects and myelosuppression is indispensable because of wide individual differences in drug tolerance.

Phase I trial of trimetrexate glucuronate on a five-day bolus schedule: clinical pharmacology and pharmacodynamics.

Trimetrexate glucuronate (TMTX), a nonclassical folate antagonist, has been evaluated clinically on several schedules. We have studied TMTX administered as an iv bolus for 5 consecutive days every 3 weeks in 35 patients with advanced solid tumors. Drug was given at doses ranging from 7.6 to 18.8 mg/m2. The maximal tolerated dose was 13.1 mg/m2 per day x 5 for patients without prior myelotoxic treatment and 7.6 mg/m2 per day x 5 for previously treated patients. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for patients not experiencing toxic effects. The dose-limiting toxicity was neutropenia. Rash and mucositis were also significant. TMTX concentrations were measured 1 and 24 hours after each dose, and the data were fit by use of a one-compartment pharmacokinetic model. With this simplified sampling and modeling scheme, the mean total body clearance (+/- SD) of trimetrexate was 31 +/- 20 mL/min per m2 and the volume of distribution was 13 +/- 7 L/m2. Mean plasma concentrations 1 hour after a dose were 1.12, 2.43, 3.33, and 3.25 mumol/L at 7.6, 9.1, 10.9, and 13.1 mg/m2, respectively. The mean TMTX concentration (+/- SD) 24 hours after a dose was 114 +/- 87 nmol/L. The mean area under the concentration-versus-time curve at 13.1 mg/m2 was 2,266 mumol.min/L. The drug concentration 1 hour after the first dose and the area under the concentration-versus-time curve were highly correlated with leukopenia and thrombocytopenia (r = .6 and .65 and P = .0007 and .0001, respectively). The maximal tolerated dose on the daily x 5 schedule was 30% of the dose tolerated on an iv bolus schedule. The choice of drug schedule for clinical trials when murine and human pharmacokinetics differ is discussed. Phase II trials are under way with both the iv bolus and the daily x 5 schedules.

A phase I trial of trimetrexate glucuronate (NSC 352122) given every 3 weeks: clinical pharmacology and pharmacodynamics.

Trimetrexate glucuronate (TMTX), a non-classic folate antagonist, has been evaluated clinically on several schedules. We studied TMTX given as an i.v. bolus over 5-30 min every 3 weeks in 44 patients with advanced solid tumors; it was given at doses ranging from 20 to 275 mg/m2. The maximal tolerated dose (MTD) on this schedule is 220 mg/m2, which we also recommend as a starting dose for phase II studies in patients without extensive prior therapy. Because of wide individual differences in drug tolerance, dose escalation in 25% increments is recommended for non-toxic patients. The principal dose-limiting toxicity was myelosuppression, although in some patients a flu-like syndrome precluded dose escalation. Significant rash and mucositis also frequently occurred in toxic patients. TMTX plasma concentrations were measured after the first dose and the data were fit by two- or three-compartment mammillary pharmacokinetic models. The TMTX clearance rate was 36.5 +/- 21 ml/min per m2 and did not change with dose; non-linearities with increasing dose were apparent in the steady-state volume of distribution (Vss) and in the terminal disposition half-life (t1/2). The difference between pre-treatment and nadir leucocyte counts was correlated with TMTX dose (r = 0.58; P = 0.0006) and with the area under the concentration vs time curve (AUC) (r = 0.41; P = 0.02). Pre-treatment plasma albumin concentrations correlated weakly with the nadir white blood count (r = -0.36; P = 0.047). Optimal schedules for the administration of TMTX have not been established and phase II trials using both bolus and daily X 5 schedules are under way.

Sedation threshold, personality, and the theory of neurosis.

For many years it has been observed that individuals differ in their tolerance of depressant drugs. In everyday life differential susceptibility to the effects of alcohol is that most commonly observed and this fact led to McDougall's early theorizing (1929) about drug tolerance and personality. Also at this time Pavlov, in dogs, recorded differences in drug sensitivity in his various temperamental types. However, the first attempt to measure individual differences in drug tolerance was made by Shagass (1954), who proposed the concept of “sedation threshold”. This was defined in terms of the amount of sodium amytal required to bring about certain behavioural and other changes in the individual, the threshold itself lying somewhere between the state of complete wakefulness and that of complete sedation. Two methods of determining the threshold were employed by Shagass. First, the point of onset of slurred speech gave an approximate estimate of its position. Secondly, a more accurate determination was made by means of EEG changes, specifically the point at which inflexion occurs in the amplitude curve of induced fast frontal activity.