Intrinsic and Extrinsic Pharmacokinetic Variability of Small Molecule Targeted Cancer Therapy

Abstract

Pharmacokinetic (PK) variability in cancer clinical trials may be due to heterogeneous populations and identifying sources of variability is important. Use of healthy subjects in clinical pharmacology studies together with detailed knowledge of the characteristics of patients with cancer can allow for quick identification and quantification of factors affecting PK variability. PK data and sources of variability of 40 marketed molecularly targeted oncology therapeutics were compiled from regulatory approval documents covering an 18‐year period (1999–2017). Variability in PK parameters was compared and contributors to variability were identified. The results show that PK variability was ~ 16% higher for peak plasma concentration (Cmax) and area under the concentration time curve (AUC) in patients with cancer compared with healthy subjects. Several factors were identified as major contributors to variability including hepatic/renal impairment and cytochrome P450 inhibition/induction. Lower PK variability in healthy subjects may represent an opportunity to perform rapid and robust pharmacological and PK assessments to inform subsequent studies in the development of new cancer therapies.

Alternatives to rifampicin: A review and perspectives on the choice of strong CYP3A inducers for clinical drug–drug interaction studies

“…The pharmacokinetics (PKs) of a drug may be influenced by extrinsic and intrinsic factors that can lead to undesired or unexpected clinical outcomes. Extrinsic factors, such as smoking habits, diet, and drug–drug interactions (DDIs) are important sources of variability in drug exposures 1 . The DDIs can inadvertently lead to exaggeration of adverse drug effects or loss of efficacy.…”

“…Extrinsic factors, such as smoking habits, diet, and drug–drug interactions (DDIs) are important sources of variability in drug exposures. 1 The DDIs can inadvertently lead to exaggeration of adverse drug effects or loss of efficacy. PK DDIs often result from inhibition and/or induction of drug metabolizing enzymes and/or transporter‐mediated disposition of a victim drug by a perpetrator drug.…”

CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene, and Pathophysiological Conditions

“…In cancer treatment phenoconversion, due both to genetic polymorphisms and clinical alterations induced by tumor itself, plays a key-role in the efficacy of therapies. Phenoconversion has the potential to influence pharmacological properties of employed drugs in terms of PK parameters, especially AUC and C max , concurring to the interindividual variability often seen among healthy subjects and patients [ 25 , 43 , 93 ].…”

Therapeutic Monitoring of Orally Administered, Small-Molecule Anticancer Medications with Tumor-Specific Cellular Protein Targets in Peripheral Fluid Spaces—A Review

“…OACDs are most often administered in one-size-fits-all doses. Nevertheless, the remarkable inter-individual variability in their pharmacokinetic properties raises the need for the individualization of OACD regimens based on the monitoring of drug exposure [ 3 ]. Therapy adherence also influences the outcome of the treatment [ 1 ].…”