Table 1.

Examples of Pharmacokinetic Boosting of Anticancer Drugs

Therapeutic Drug	Boosting Agent	Suggested Mechanism	Impact of Boosting on Bioavailability	Impact of Boosting on Variability	Latest Phase of Clinical Development	Ref
Etoposide	Ketoconazole	P-gp UGT1A1 CYP3A4	20% increase in AUC	Increased from 43% to 89%	I	[37]
Etoposide	Grapefruit Juice	P-gp CYP3A4	26% decrease in AUC	Increased from 38% to 53%	I	[36]
Topotecan	Elacridar (GF120918)	P-gp BCRP	Increased oral bioavailability from 40% to 97%	Decreased from 17% to 11%	I	[40]
Paclitaxela	Cyclosporin	P-gp CYP3A4	Increased oral bioavailability from <10% to 28%	Remained ~50%	I	[65]
Paclitaxela	Ritonavir	P-gp CYP3A4	Unclear; Paclitaxel exposure is similar when given with ritonavir or cyclosporin	Unclear	II	[47,66]
Paclitaxela	Elacridar (GF120918)	P-gp BCRP	Increased oral bioavailability from <10% to 50%	Remained ~50%	I	[67]
Paclitaxela	Encequidar (HM30181A)	P-gp	Unclear, but bioequivalent to single dose of IV paclitaxel 80mg/m2	Unclear	III	[45]
Docetaxel	Cyclosporin	P-gp CYP3A4	Increased oral bioavailability from 8% to 90%	Decreased from 90% to 67%	I	[68]
Docetaxel	Ritonavir	P-gp CYP3A4	Increased oral bioavailability from <10% to 161%↑	Decreased from ~90% to 44% – 70%	II	[46,69]
Docetaxel (Oradoxel)	Encequidar (HM30181A)	P-gp	Ongoing	Ongoing	I	[70]b
Docetaxel	ONT-093	P-gp	Increased oral bioavailability from <10% to 26%	Decreased from ~90% to 31%	I	[71]
1-ethoxymethyl derivative of 5-FU	CNDP	DPD	Increased AUC	Decreased	II	[72]
5-FU	Eniluracil	DPD	Bioavailability of 5-FU is increased to virtually 100%, increased half-life by 20-fold, decreased clearance by 20-fold	Decreased to 20%	II	[73,74]
5-FU (Tegafur)	Uracil	DPD	Comparable levels of 5-FU in normal tissues and plasma, but 5- to 10-fold greater concentrations of 5-FU in tumor tissues	Remained ~50%	Approved (MHLW)	[75,76]
5-FU (Tegafur)	Gimeracil/Oteracil	DPD	Increased AUC by 6-fold	Decreased to 35%	Approved (EMA, MHLW)	[74]
Trifluridine	Tipiracil	TD	Increased AUC by 38-fold	Unclear	Approved (FDA, EMA, MHLW)	[77]
Decitabine	Cedazuridine	CD	Unclear, but bioequivalent to single dose of IV decitabine 20mg/m2	Unclear	Approved (FDA, EMA)	[38]
Axitinib	Cobicistat	CYP3A	Case Studyb	Case Studyb	Case Studyb	[55]
Crizotinib	Cobicistat	CYP3A	Case Studyb	Case Studyb	Case Studyb	[56]
Ibrutinib	Itraconazole	CYP3A	Increased dose-adjusted AUC 10-fold	Decreased from 104% to 55%	I	[26]

^aIntravenous paclitaxel exhibits nonlinear pharmacokinetics due to Cremophor EL, a co-solvent, that is not absorbed orally. While each of these inhibitors increases exposure to oral paclitaxel, it is more complicated to interpret the impact of each of these inhibitors on paclitaxel’s bioavailability/variability [2].

^bCase study unable to determine impact on bioavailability and variability