Gender differences in pharmacokinetics and pharmacodynamics

I. Beierle, Bernd Meibohm, H. Derendorf

Research output: Contribution to journalReview article

169 Citations (Scopus)

Abstract

Several years ago regulatory authorities requested to include women in all phases of clinical drug development in order to thoroughly investigate potential gender differences in the pharmacokinetics and pharmacodynamics of newly developed therapeutic agents. Since then, numerous reports have been published that evaluate the potential existence and impact of gender differences on all aspects of clinical pharmacology. With regard to pharmacokinetics, differences in absorption rate and duration have been reported for several drugs, but generally lack to have major clinical relevance. Differences in oral bioavailability, however, seem to be more important and are usually caused by sex differences in the activity of major intestinal and hepatic metabolic enzymes. Distributional differences have also been identified for numerous compounds. Although the majority of these findings were merely weight effects as women generally have a lower body weight, some of the gender-specific distribution differences persisted after normalization for weight. Possible explanations are differences in body composition between men and women and/or physiological changes during the menstrual cycle as well as differences in plasma protein binding secondary to hormonal characteristics. Frequent and sometimes clinically relevant gender differences could be identified for drug elimination processes and were predominantly linked to the sex-specific expression of metabolic enzyme systems, e.g. CYP3A4 and CYP1A2. In contrast, gender-related differences in renal elimination are generally only of minor importance. With regard to pharmacodynamics, gender differences have been observed in baseline characteristics as well as in drug response, which might both, at least in part, be the consequence of modulation by sex hormones. Some of the most striking examples identified were in pain therapy and perception, glucose management and arrhythmia susceptibility. Since clinical endpoints of efficacy and toxicity are often difficult to monitor and are frequently substituted by surrogate markers that might increase variability and thus mask gender effects, sex-specific differences in pharmacodynamic characteristics can often remain uncovered and further intensive research in this area seems imperative. For the majority of investigated drugs in the past few years, however, no or only very minor gender differences could be detected in pharmacokinetics and/or pharmacodynamics. In addition, the clinical significance of those gender differences identified seem very limited and was only very rarely linked to treatment success or failure. Hence, it is undoubtedly necessary to include women in the clinical drug development process, but it seems questionable whether women of child-bearing capability should be exposed to potential risks in early phase I clinical trials.

Original languageEnglish (US)
Pages (from-to)529-547
Number of pages19
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume37
Issue number11
StatePublished - Nov 19 1999

Fingerprint

Pharmacokinetics
Pharmaceutical Preparations
Sex Characteristics
Weights and Measures
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP1A2
Clinical Trials, Phase I
Pain Perception
Clinical Pharmacology
Gonadal Steroid Hormones
Enzymes
Menstrual Cycle
Masks
Body Composition
Protein Binding
Biological Availability
Cardiac Arrhythmias
Blood Proteins
Therapeutics
Biomarkers

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Pharmacology
  • Pharmacology (medical)

Cite this

Gender differences in pharmacokinetics and pharmacodynamics. / Beierle, I.; Meibohm, Bernd; Derendorf, H.

In: International Journal of Clinical Pharmacology and Therapeutics, Vol. 37, No. 11, 19.11.1999, p. 529-547.

Research output: Contribution to journalReview article

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