Fixed dose method

Acute Oral Toxicity - Fixed Dose Method (Updated Guideline, adopted 20 December 2001)... 

Acute oral toxicity - Fixed dose method 2001... 

The guidance document offers a comparison of TG 420 (Fixed Dose Method), TG 423 (Acute Toxic Class Method), and TG 425 (Up-and-Down Procedure). The purpose of this Guidance Document is to provide information to assist with the choice of the most appropriate Guideline to enable particular data requirements to be met while reducing the number of animals used and animal suffering. The Guidance Document also contains additional information on the conduct and interpretation of test guidelines 420, 423, and 425. 

As mentioned above, a NOAEL is usually not derived in acute toxicity smdies. It is more usual that the only numerical value derived is the LD50 or LC50 value. The LD50 or LC50 values (or the discriminating dose if the Fixed Dose Procedure was used or the result of the Acute Toxic Class Method) give an indication of the relative lethal potency of a substance. The slope of the dose-response curve is a particularly useful parameter as it indicates the extent to which reduction of exposure will reduce the lethality the steeper the slope, the greater the reduction in response for a particular finite reduction in exposure. 

The Committee noted that dissolution test methods were being developed and agreed that rifampicin should serve as the marker for dissolution testing in the relevant fixed-dose combinations, as it was the least soluble substance. For other products, standard dissolution test methods could be applied. 

If the pharmacokinetic bioequivalence of fixed-dose combination (FDC) products is assessed by in vivo studies the study design should follow the same general principles as described in previous sections. The multisource FDC product should be compared with the pharmaceutically equivalent comparator FDC product. In certain cases (e.g. when no comparator FDC product is available on the market) separate products administered in free combination can be used as a comparator (5). Sampling times should be chosen to enable the pharmacokinetic parameters of all APIs to be adequately assessed. The bioanalytical method should be validated on respect... 

Panchagnula R, Agrawal S, Ashokraj Y, et al. Fixed dose combinations for tuberculosis lessons learned from clinical, formulation and regulatory perspective. Methods Find Exp Clin Pharmacol 2004 Nov 26(9) 703- 721. 

Buoen et al. (9) reported that the dose-escalation schemes used in FTIH studies could be categorized as linear, logarithmic, modified Fibonacci, or miscellaneous. The latter included dose-escalation regimens in which the three standardized methods are combined. The authors reported that in 12 out of the 105 studies they reviewed a linear escalation method with fixed dose increment was used. A logarithmic dose-escalation scheme in which the relative dose increment was the same (e.g., 100%) was used in 22 studies. Four of the studies used a modified version of the Fibonacci escalation scheme, which is frequently used in cancer Phase 1 trials (6, 12-14). For most of the studies reviewed (i.e., 63.8%, or 67 studies) the dose-escalation schemes used did not seem to follow one particular scheme. In some cases two of the escalation schemes described above were combined (e.g., starting with a logarithmic escalation to convert later into a modified Fibonacci sequence), while for other studies, no escalation scheme was apparent. The doses appeared to have been chosen arbitrarily (11). 

A common approach to Graves hyperthyroidism is to administer a single dose of 5 to 15 mCi(80 to 120 mcCi/g of tissue). ° The optimal method for determining 1 treatment doses for Graves hyperthyroidism is unknown, and techniques have varied from a fixed dose to more elaborate calculations based on gland size, iodine uptake. 

The two main methods of aerosol delivery in capsaicin (and cinic acid) cough challenge testing are the single-dose and dose-response methods (Morice et al. 2001). In the single-dose method, one specific concentration of capsaicin is utilized. Typically, the number of coughs induced by a fixed time period of tidal breathing would be determined. 

The treatment of tuberculosis still largely relies on the use of rifampin, isoniazid, pyrazinamide, and ethambutol HCl. Although the chromatographic analysis of these drugs is well established, the recently notified USP gradient HPLC method for quantitative determination of rifampicin, isoniazid, and pyrazinamide in fixed-dose combination (FDC) formulations has enhanced our analytical capability to ensure the quality of these products. 

Nitrogen isotherms were obtained with a Coulter Omnisorp 360 system. All samples were ground into a powder and degassed at 150 C overnight A fixed dosing (75 torr for each dose) method was used to acquire a full isotherms. The specific surface area was calculated by the BET method. 

In testing intrinsic factor preparations unreliable subjects can be excluded and fecal excretion methods are satisfactory. The technique of Baker and Mollin (1955) is particularly suitable. With the use of a fixed dose of Co -labeled B12, two intrinsic factor preparations can be tested in parallel in successive weeks in the same patient over a range of doses wide enough to permit comparison of the absorption gradients obtained for each of the preparations (page 163). 

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