Concentration-time profiles bioequivalence

Also, if conversion of drug to active metabolite shows significant departure from linear pharmacokinetics, it is possible that small differences in the rate of absorption of the parent drug (even within the 80-125% range for log transformed data) could result in clinically significant differences in the concentration/ time profiles for the active metabolite. When reliable data indicate that this situation may exist, a requirement of quantification of active metabolites in a bioequivalency study would seem to be fully justified. 

Assay performance criteria for biopharmaceuticals are often highly variable therefore strict statistical criteria that attempt to rigorously establish traditional in vivo bioequivalence may not always be appropriate. In some cases an assessment of rate and extent of absorption as indicated by the maximum concentration (Cmax), time of maximum concentration (Tmax) and area under the curve (AUC) may be needed. In other cases complicating factors related to binding proteins, endogenous concentration, and unusual concentration-time profiles may need to be considered [15]. In cases where complications may arise from immune response to heterologous proteins, cross-over designs are inappropriate. 

The mean concentration-time profiles for each of the four analytes, and for each of the two formulations, generated by this study are shown in Fig. 7. The pharmacokinetic comparisons derived from this study for all four analytes are summarized in Table 4. As can be seen from Fig. 7 and Table 4, a four-way bioequivalence assessment proved both feasible and practical. This study also demonstrated that si ar formulations will produce similar concentration-time profiles for all the enantiomers in the plasma (even given lot-to-lot variability, manufacturing site-to-site variability, and shelf-time variability). 

When assessing bioequivalence, the following three parameters that characterize the plasma or blood concentration-time profile of the administered drug are usually measured ... 

For many pharmaceutical compounds administered as transdermal drug delivery systems, absorption can be assessed by determining the area under the curve (AUC) of the plasma concentration-time profile, the peak plasma flux, and time of peak flux, much as it is for determining bioavailability from oral and other routes of administration. These are classical metrics of biophar-maceutical bioequivalence studies and are extensively covered in other texts... 

Generally, evaluation of pharmacokinetic bioequivalence will be based upon the measured concentrations of the parent drug released from the dosage form rather than the metabolite. The concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution and elimination. It is important to state a priori in the study protocol which chemical entities (pro-drug, drug (API) or metabolite) will be analysed in the samples. 

If pharmacokinetics are dependent on dose or time, or a slow-release formulation is being studied, it is necessary to examine bioequivalence at steady state. For controlled-release formulations which are intended to produce relatively flat concentration-time profiles, an index of fluctuation is required, for example - Cn,jj])/C. A study at steady state may also be needed if the assay is not sensitive enough to quantify plasma concentrations of drug up to four half-lives after a single dose. Sometimes it is not technically feasible to assay a drug in plasma and it may then the justifiable to compare bioavailability by the total amount of drug excreted in urine, or pharmacodynamic data may be used, but these cases are exceptions. 

Level A correlation is generally the most desirable form, since the in vitro method completely mimics the in vivo results, and a direct correspondence exists at each time point. The achievement of an in vitro method that models the entire in vivo process confers confidence in the method s capability as a surrogate for in vivo studies. This allows for predictions from in vitro data of complete absorption-time and plasma concentration-time profiles in early formulation development as well as in later phases, when relevant in vitro specification limits are settled. In addition, it is only level A correlations that are accepted by regulatory agencies as a basis for replacing in vivo bioequivalence studies with in vitro dissolution tests. 

When introducing new formulations of a drug we may have considerable information already available on a standard formulation. It may thus be of interest to establish what dose of the new formulation has the same response as the standard. In some cases this can be handled in a way similar to that conventionally used for bioequivalence. That is to say, the bioavailability of the standard formulation and an assumed dose form for the new formulation can be established by studying the concentration-time profiles. The bioavailability of the new formulation can then be adjusted according to these results. 

This sort of choice between models occurs all the time in PK/PD work. This is because even where, and unlike the example above, a subject or patient is given a single treatment, repeated blood samples are taken and we wish to use the observed concentration -time profiles to estimate particular parameters. We thus have a repeated-measures problem. Often a summary-measures approach is used. For example, in bioequivalence studies AUCs are compared for different formulations. These AUCs are always calculated first for each subject before proceeding to the modelling process. On the other hand, in certain applications it is not possible to cover all desired blood sampling points in all patients. Different times are used for different patients to minimize the number of samples taken. The only way in which this can be drawn together is via a random-effects approach. 

Figure 8.6 Plasma concentration versus time profiles obtained following administration of different transdermal nitroglycerin systems for 24 hours (Modified from Transdermal Delivery Systems A Medical Rationale. Cleary, G.W. In Topical Drug Bioavailability, Bioequivalence, and Penetration. Shah, V.P. and Maibach, H.I. Eds. Plenum Press, New York, 1993, pp 17-68)...

To ensure interchangeability, the multisource product must be therapeutically equivalent to the comparator product. Types of in vivo bioequivalence studies include pharmacokinetic studies, pharmacodynamic studies and comparative clinical trials. Direct practical demonstration of therapeutic equivalence in a clinical study usually requires large numbers of patients. Such studies in humans can be financially daunting, are often unnecessary and may be unethical. For these reasons the science of bioequivalence testing has been developed over the last 40 years. According to the tenets of this science, therapeutic equivalence can be assured when the multisource product is both pharmaceutically equivalent/alternative and bioequivalent. Assuming that in the same subject an essentially similar plasma concentration time course will result in essentially similar concentrations at the site(s) of action and thus an essentially similar therapeutic outcome, pharmacokinetic data may be used instead of therapeutic results. In selected cases, in vitro comparison of dissolution profile of the multisource product with that of the comparator product, or dissolution studies, may be sufficient to provide indication of equivalence. 

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