Multiple dose safety study

A multiple-dose safety study typically is initiated once the first study in humans is completed. The primary goal of the second study is to define an MTD with multiple... 

Children Two hundred fifty-one patients 4 years of age and above have received amprenavir as single or multiple doses in studies. An adverse event profile similar to that seen in adults was seen in pediatric patients. The safety, efficacy, and pharmacokinetics of amprenavir capsules have not been evaluated in pediatric patients below 4 years of age. 

The pharmacokinetic evaluation of biopharmaceuticals is generally simplified by the usual metabolism of products to small peptides and to amino acids, and thus classical biotransformation and metabolism studies are rarely necessary. Routine studies to assess mass balance are not useful. However, both single- and multiple-dose toxicokinetic data are essential in safety pharmacology asessments, and these can be complicated by two factors (1) biphasic clearance with a saturable, initial, receptor-dependent clearance phase, which may cause nonlinearity in dose-exposure relationships and doseresponses [14] and (2) antibody production against an antigenic biopharmaceutical that can alter clearance or activity in more chronic repeat-dose safety studies in the preclinical model. 

Russell D, Bakhtyari A, Jazrawi RP, Whitlock L, Ridgway C, McHale M, Abel S (2003) Multiple dose study to investigate the safety of UK-427,857 (100 mg or 300mg) BID for 28 days in healthy males and females. In 43rd interscience conference on antimicrobial agents and chemotherapy, Chicago, IL, USA... 

Estimation of Initial Safety and Tolerability. The initial and subsequent administration of an investigational new drug into humans is usually intended to determine the tolerability of the does range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. These studies typically include both single and multiple dose administration. 

Following construction, characterization, and scale-up of trastuzumab, phase I testing of the humanized mAh was carried out in patients with HER2-overexpressing metastatic breast cancer. The initial phase I study evaluated the safety and pharmacokinetics of a single, escalating (10-500 mg) intravenous dose of trastuzumab. A subsequent phase I study evaluated the safety and pharmacokinetics of multiple-dose administration, with weekly intravenous doses and similar dose escalation by cohort (10-500 mg). Both studies of 32 patients overall demonstrated that trastuzumab monotherapy was very well tolerated, with no serious adverse events attributable to mAh treatment. A third phase I study included trastuzumab, again via weekly intravenous administration of 10-500 mg, in combination with cisplatin chemotherapy at 50 or 100 mg/m2 per 4-week cycle. Toxicities in this trial were those commonly seen with cisplatin. 

Acute oral toxicity is the study of adverse effects occurring shortly after oral administration of a single chemical dose or multiple doses given to an animal within 24 hours. In the evaluation of chemical safety, determination of acute oral toxicity becomes important, since it normally forms the first study step. Acute toxicity is important in establishing dose regimen for subchronic and other studies, and may provide initial information on the mode of chemical toxic action, as well as a basis of for classification and labeling. 

Whereas many CNS safety tests evaluate multiple doses, we recommend the inclusion of just two doses for non-precipitated withdrawal studies. The low dose should be close to the dose inducing clear effects in the test predictive of the substance s therapeutic indication. The high dose should be the maximally tolerated dose as determined, for example, from an Irwin test. If it can be shown that the test substance can be repeatedly administered at a maximally tolerated dose under conditions where similar treatment with an appropriately chosen reference substance induces... 

At the end of such multiple dose studies the animals are killed in terminal anesthesia and maximal blood collection is possible. Therefore, not only the target metabolic parameters (e.g. glucose, lactate, free fatty acids, triglycerides, cholesterol) but also other parameters, which reflect intermediary metabolism (e.g. keton bodies, urea, uric acid) as well as safety parameters (e.g. ASAT, ALAT, AP, LDH) can be determined by clinical chemistry. 

The additional anti-atherosclerotic potential of a candidate compound with a different primary indication does not represent a safety concern. In contrast, the atherogenic potential of a candidate compound, identified during safety pharmacological evaluation, represents a serious safety issue. Development of atherosclerosis needs time and therefore multiple dose studies are necessary to detect a putative anti-atherosclerotic or atherogenic side effect potential of a candidate compound. 

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