International Journal of Pharmaceutics 201 (2000) 131 – 150 www.elsevier.com/locate/ijpharm
Biopharmaceutics and pharmacokinetics in drug research
Ramesh Panchagnula *, Narisetty Sunil Thomas
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India
Received 7 September 1999; received in revised form 6 January 2000; accepted 6 January 2000
With the synergistic and multiplicative interactions of rational drug design, recombinant biotechnology, combinatorial chemistry and high-throughput screening, millions of compounds are being synthesized by chemists. However, development of these drug candidates has often been impeded, if not terminated, due to biopharmaceutic and/or pharmacokinetic constraints. This has resulted in delays in development time and escalation of cost in the drug research programmes. So, the present emphasis is to reduce development time and cost, which is analogous to added patent life besides the enormous reduction in human suffering. In this compilation the important biopharmaceutic and pharmacokinetic approaches are discussed, which will help in the development of safe and more efﬁcacious drugs with reduced development time and cost. © 2000 Elsevier Science B.V. All rights reserved. Keywords: New drug development; Biopharmaceutics; Pharmacokinetics; Solubility; Permeability; Lipophilicity
Drug research is a unique multi-disciplinary
process heading towards the development of novel
therapeutic agents in areas of currently unmet
medical need. The drug research can be divided
functionally into two stages: discovery/design and
development (Fig. 1). Drug discovery/design consists of identiﬁcation and characterization of new targets (enzymes or receptors), synthesis of new
* Corresponding author. Tel: + 91-172-673848; fax: +91172-677185. E-mail address: firstname.lastname@example.org (R. Panchagnula)
lead molecules, screening of new lead molecules
for in vitro and/or in vivo biological activities,
and physicochemical characterization of leads.
Drug development focuses on evaluation of
safety/toxicity and efﬁcacy of new drug molecules.
The key objective of drug development is the
generation of a scientiﬁc database that supports
the effectiveness and safety proﬁle of the dosage
regimen(s) intended for marketing. On an average
every new drug molecule requires 12–15 years to
reach the patient and costs a staggering amount
of US$ 400–650 million (Collins et al., 1999).
Although new methods, such as pharmacophore theory and molecular modeling, are be-
0378-5173/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S 0 3 7 8 - 5 1 7 3 ( 0 0 ) 0 0 3 4 4 - 6
R. Panchagnula, N.S. Thomas / International Journal of Pharmaceutics 201 (2000) 131–150
Fig. 1. Various stages of drug research.
ing used to assist rational drug design, the classical method of choosing potential drugs for drug development in the pharmaceutical industry still
relies on an evaluation of pharmacodynamic activity in vitro and/or in animal models. However, majority of the drug molecules fail in subsequent
drug development program because the efﬁcacy
and safety are not governed by its pharmacodynamic characteristics alone. It also depends to a large degree on the biopharmaceutical (e.g. solubility, stability, permeability and ﬁrst pass effect) and pharmacokinetic (clearance rate, biological
half-life, extent of protein binding and volume of
distribution) properties of the drug, since these
properties control the rate and the extent to which
the drug can reach its site of action, i.e. biophase.
Some data on reasons for withdrawal of
candidate drugs from development has been
published by the Center for Medicines
Research (Prentis et al., 1988), which says that
nearly 40% of the drugs (78 of 198 compounds)
were terminated from further development due
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