Pharmacokinetic Drug Interactions of Gefitinib with Rifampicin, Itraconazole and Metoprolol

Abstract

Although CYP3A4 inducers may reduce exposure to gefitinib, further work is required to define any resultant effect on the efficacy of gefitinib. Exposure to gefitinib is increased by coadministration with CYP3A4 inhibitors, but since gefitinib is known to have a good tolerability profile, a dosage reduction is not recommended. Gefitinib is unlikely to exert a clinically relevant effect on the pharmacokinetics of drugs that are dependent on CYP2D6-mediated metabolism for their clearance, but the potential to increase plasma concentrations should be considered if gefitinib is coadministered with CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated.

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

“…After dosing of 600 mg q.d. of RIF for 8 to 10 days in human subjects, the average plasma unbound concentration reached 0.5 to 1.5 M (Borin et al, 1997;Swaisland et al, 2005). This concentration is much higher than its in vitro unbound EC 50 for induction of 0.1 to 0.2 M, suggesting that at doses of 600 mg and higher CYP3A4 induction is saturated by RIF in vivo.…”

Gefitinib accumulation in glioblastoma tissue

“…We propose that several mechanisms converge to achieve such high drug accumulation: (1) small size of gefitinib facilitates tumor access by diffusion; 16 (2) its high water solubility enables thermodynamic retention inside the malignant cells; 24 (3) low CYP3A4 activity in GBM tissue, the main enzyme for gefitinib catabolism, 13 prevents metabolic elimination.…”

“…Patients on cytochrome P450 isoenzyme CYP3A4-inducing antiepileptic drugs (EIAE) are excluded due to predicted ensuing interactions of these drugs with gefitinib metabolism, reducing systemic availability. 12,13 After giving written informed consent, patients receive gefitinib 500 mg daily starting at least five days prior to re-operation, allowing to approach steady state tissue and plasma levels, as determined in prior trials. 34 The treatment continues until tumor progression or occurrence of intolerable side effects.…”

“…These include the intrinsic resistance of malignant cells to radiation and chemotherapy resulting from high DNA repair capacity [1][2][3] and tumor hypoxia; 4,5 the iatrogenic induction of biochemical, cellular and molecular treatment resistance caused by glucocorticoid (GC) administration; 6,7 apoptosis resistance; 8,9 absence or mutation of molecular drug targets; 10,11 enhanced drug metabolism; 12,13 and also restricted drug access. Indeed, there are several obstacles to drug access to tumor cells, as an intact blood brain barrier (BBB), 14,15 vascular and interstitial barriers [16][17][18] and clearing by MDR1 and other ABC transporter proteins.…”

Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole

“…[15,23,24] Based on the t ½ of itraconazole (»36 hours at steady state), it has been predicted that its CYP3A4 inhibitory effect continues for about 2 weeks after the last dose. [25] Thus, the extended washout period used in this study (3 months) was considered adequate to dissipate the action of itraconazole. Coadministration with itraconazole resulted in a small, statistically significant increase (9%) in exposure to vandetanib as assessed by AUC 504 , probably due to reduced metabolic clearance consistent with CYP3A4 inhibition.…”