Abstract
Regulatory assessment of bioavailability and bioequivalence in the US frequently relies on measures of rate and extent of absorption. Rate of absorption is not only difficult to measure but also bears little clinical relevance. This paper proposes that measures of bioavailability and bioequivalence for drugs that achieve their therapeutic effects after entry into the systemic circulation are best expressed in terms of early [partial area under the concentration-time curve (AUC)], peak plasma or serum drug concentration and total AUC exposure for a plasma or serum concentration-time profile. With suitable documentation, these systemic exposure measures can be related to efficacy and tolerability outcomes. The early measure is recommended for an immediate release drug product where a better control of drug absorption is needed, for example to ensure rapid onset of a therapeutic effect or to avoid an adverse reaction from a fast input rate. The 3 systemic exposure measures for bioavailability and bioequivalence studies can provide critical links between product quality and clinical outcome and thereby reduce the current emphasis on rate of absorption.
Similar content being viewed by others
References
US Department of Health and Human Services, Food and Drug Administration, Federal Food, Drug and Cosmetic Act, as Amended and Related Laws, 86-1051, Section 505 (j)(7)(B); codified as 21 USC (U.S. Code) 355 (j)(7)(B). Washington, DC: U.S. Government Printing Office, 1986: 66
Aarons L. Assessment of rate of absorption in bioequivalence studies. J Pharm Sci 1987; 76: 853–5
Endrenyi L, Fritsch S, Yan W. Cmax/AUC is a clearer measure than Cmax for absorption rates in investigations of bioequivalence. Int J Clin Pharmacol Ther Toxicol 1991; 29: 394–9
Schall R, Luus HE. Comparison of absorption rates in bioequivalence studies of immediate release drug formulations. Int J Clin Pharmacol Ther Toxicol 1992; 30: 153–9
Chen ML. An alternative approach for assessment of rate of absorption in bioequivalence studies. Pharm Res 1992; 9: 1380–5
Bois FY Tozer TN, Hauck WW, et al. Bioequivalence: performance of several measures of extent of absorption. Pharm Res 1994; 11: 715–22
Bois, FY, Tozer TN, Hauck WW, et al. Bioequivalence: performance of several measures of rate of absorption. Pharm Res 1994; 11: 966–74
Lacey LF, Keene ON, Duquesnoy C, et al. Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies. J Pharm Sci 1994; 83: 212–5
Reppas C, Lacey LF, Keene ON, et al. Evaluation of different metrics as indirect measures of rate of drug absorption from extended release dosage forms at steady-state. Pharm Res 1995; 12: 103–7
Endrenyi L, Al-Shaikh P. Sensitive and specific determination of the equivalence of absorption rates. Pharm Res 1995; 12: 1856–64
Gibaldi M, Perrier D, editors. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, Inc., 1982
Chen ML, Chiou WL. Assessment of rate of absorption in bioequivalence studies. Chinese Pharm J 1992; 44: 173–83
Schuirmann DJ. A comparison of the two one-sided tests pro cedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987; 15: 657–80
Nightingale SL, Morrison JC. Generic drugs and the prescribing physicians. JAMA 1987; 258 (9): 1200–4
Veng-Perdersen P, Tillman LG. Center of gravity of drug level curves: a model-independent parameter useful in bioavailability studies. J Pharm Sci 1989; 78: 848–54
Benet LZ, Chiang CWN. APhA Academy of Pharmaceutical Sciences, 13th National Meeting [abstracts of papers]; 1972; Chicago. Vol. 2. Chicago (IL): Academy of Pharmaceutical Sciences, 1972: 169
Gamel J, Rousseau WF, Katholi CR, et al. Pitfalls in digital computation of the impulse response of vascular beds from indicator-dilution curves. Circ Res 1973; 32: 516–23
Vaughan DP, Dennis M. Mathematical basis of point-area deconvolution method for determining in vivo input functions. J Pharm Sci 1978; 67: 663–5
Cutler DJ. Numerical deconvolution by least squares: use of prescribed input functions. J Pharmacokinet Biopharm 1978; 6: 227–41
Cutler DJ. Numerical deconvolution by least squares: use of polynomials to represent the function. J Pharmacokinet Biopharm 1978; 6: 243–63
Vaughan DP. Approximation in point-area deconvolution algorithm as mathematical basis for empirical instantaneous midpoint-input deconvolution method. J Pharm Sci 1981; 70 (7): 831–2
Charter MK, Gull SF. Maximum entropy and its application to the calculation of drug absorption rate. J Pharmacokinet Biopharm 1987; 15: 645–55
Chan KK, Langenbucher F, Gibaldi M. Evaluation of in vivo drug release by numerical deconvolution using oral solution data as weighting function. J Pharm Sci 1987; 76 (6): 446–50
Williams RL. Bioequivalence and therapeutic equivalence. In: Welling PG, Tse FLS, Dighe SV, editors. Pharmaceutical bioequivalence. New York: Marcel Dekker, Inc., 1991: 1–16
Jackson AJ, Chen ML. Application of moment analysis in assessing rates of absorption for bioequivalence studies. J Pharm Sci 1987; 76: 6–9
Endrenyi L, Yan W. Variation of Cmax and Cmax/AUC in investigations of bioequivalence. Int J Clin Pharmacol Ther Toxicol 1993; 31: 184–9
Tothfalusi L, Endrenyi L. Without extrapolation, Cmax/AUC is an effective metric in investigations of bioequivalence. Pharm Res 1995; 12: 937–42
Tozer TN, Bois FY, Hauck WW, et al. Absorption rate vs. exposure: which is more useful for bioequivalence testing? Pharm Res 1996; 13: 453–6
Basson RP, Cerimele BJ, DeSante KA, et at. Tmax: an unconfounded metric for rate of absorption in single dose bioequivalence studies. Pharm Res 1996; 13: 324–8
Rostami-Hodjegan A, Jackson PR, Tucker GT. Sensitivity of indirect metrics for assessing ‘rate’ in bioequivalence studies — moving the ‘goalposts’ or changing the ‘game’. J Pharm Sci 1994; 83: 1554–7
Rosenbaum SE, Rhodes CT, Bon C. Area under the curve estimation in bioequivalence studies. Drug Dev Ind Pharm 1990; 16: 157–63
Macheras P, Symillides M, Reppas C. The cutoff time point of the partial area method for assessment of rate of absorption in bioequivalence studies. Pharm Res 1994; 11: 831–4
Endrenyi L, Csizmadia F, Tothfalusi L, et al. The duration of measuring partial AUCs for the assessment of bioequivalence. Pharm Res 1998; 15: 399–404
Endrenyi L, Csizmadia F, Tothfalusi L, et al. Metrics comparing simulated early concentration profiles for the determination of bioequivalence. Pharm Res 1998; 15: 1292–9
Macheras P, Symillides M, Reppas C. An improved intercept method for the assessment of absorption rate in bioequivalence studies. Pharm Res 1996; 13: 1755–8
Midha KK, Hubbard JW, Rawson M, et al. The partial areas in assessment of rate and extent of absorption in bioequivalence studies of conventional release products: experimental evidence. Eur J Pharm Sci 1994; 2: 351–63
Endrenyi L, Tothfalusi L. Truncated AUC evaluates effectively the bioequivalence of drugs with long half-lives. Int J Clin Pharmacol Ther 1997; 35: 142–50
Gaudreault J, Potvin D, Lavigne J, et al. Truncated area under the curve as a measure of relative extent of bioavailability evaluation using experimental data and Monte Carlo simulation. Pharm Res 1998; 15 (10): 1621–9
Evans WE, Crom WR, Stewart CF, et al. Clinical pharmacody namics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl J Med 1986; 314 (8): 417–7
Egorin MJ, Reyno LM, Canetta RM, et al. Modeling toxicity and response in carboplatin-based combination chemotherapy. Semin Oncol 1994; 21 (5 Suppl. 12): 7–19
Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dos age: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748–56
Rodman JH, Abromowitch M, Sinkule JA, et al. Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a phase I trial. J Clin Oncol 1987; 5: 1007–14
Desai ZR, Van den Berg HW, Bridges JM, et al. Can severe vincristine neurotoxicity be prevented? Cancer Chemother Pharmacol 1982; 8: 211–4
Preston SL, Drusano GL, Berman AL, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA 1998; 279: 125–9
Schentag JJ. Antibiotic dosing: does one size fit all? JAMA 1998; 279: 159–60
Goss TF, Forrest A, Nix DE, et al. Mathematical examination of dual individualization principles II: the rate of bacterial eradication at the same area under the inhibitory curve (AUIC) is more rapid for ciprofloxacin than for cefmenoxime. Ann Pharmacother 1994; 28: 863–8
US Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products — general considerations. Rockville (MD): Office of Training and Communications, Division of Communications Management, Drug Information Branch, 2000 Oct
Fossler MJ, Chen ML. Early exposure in bioequivalence: evaluation of statistical criteria using clinical trial simulation [abstract 4150]. AAPS PharmSci 1999; 1 Suppl.: S636
Pollak PT, Freeman DJ, Carruthers SG. Mean apical concentration and duration in the comparative bioavailability of slowly absorbed and eliminated drug preparations. J Pharm Sci 1988; 77: 477–80
Acknowledgements
The authors wish to acknowledge Drs Thomas Tozer, Frederic Bois, Laszlo Endrenyi, Michael Fossler, Alfred Balch, Chuanpu Hu, William Gillespie, Donald Schuirmann, Rabindra Patnaik and Dale Conner, as well as the members of the FDA Metrics Working Group for their contributions to the deliberation of this topic. The current members of the FDA Metrics Working Group are Mei-Ling Chen (Chair), Barbara Devit, Mamata Gokhale, Yih-Chain Huang, Ajaz Hussain, Peter Lee, Zakaria Wahba and Dan Wang.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chen, ML., Lesko, L. & Williams, R.L. Measures of Exposure versus Measures of Rate and Extent of Absorption. Clin Pharmacokinet 40, 565–572 (2001). https://doi.org/10.2165/00003088-200140080-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200140080-00001