Impact of dosage timing on the bioavailability of oral anticancer medications: Is pre-prandial dosing equivalent to post-prandial dosing

A majority of oral anticancer drugs are instructed to be given without regard to food intake according to the prescribing information. Even when some drugs are indicated to be taken without food, either at least 1 h before or 2 h after food is generally recommended. Nonetheless, it is largely unclear as to whether different timings of an oral anticancer agent administration in relation to food intake would lead to different efficacy or safety profiles. Recently, post-prandial dosing has been shown to provide substantially higher plasma lapatinib concentrations than pre-prandial dosing, ¹ raising the concern that the dosage timing with respect to food would greatly affect bioavailability and plasma concentrations of a specific anticancer agent, and subsequently, result in suboptimal treatment outcomes.

To revisit the effect of dosage timing on the bioavailability and plasma drug concentrations of a specific anticancer medication between the labeled pre-prandial and post-prandial conditions, we conducted a literature survey and labeling analysis for oral anticancer drugs approved by the US Food and Drug Administration (FDA) from January 2010 to December 2016. There were 44 oral anticancer drugs (Table 1) approved during the period according to the 140 approval records in the FDA dataset of Hematology/Oncology (Cancer) Approvals.^2–6 Public available regulatory review and the latest prescribing information for these drugs were extracted from the Drug@FDA database (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm). The literature pertaining to the dosage timing in relation to food was captured using PubMed.

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Table 1.

Oral anticancer agents approved by the US Food and Drug Administration from 2010 to 2016.^2–6

Drug	Year	Action of approval	Indication
Rucaparib	2016	Accelerated approval	Ovarian cancer with deleterious BRCA mutation
Erlotinib	2016	Modified the indication	Non-small cell lung cancer (NSCLC) with specific EGFR mutations
Lenvatinib	2016	Approval for use in combination with everolimus	Renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
Cabozantinib	2016	Approval	RCC following prior anti-angiogenic therapy
Venetoclax	2016	Approval	Chronic lymphocytic leukemia (CLL) with 17 p deletion
Crizotinib	2016	Approval	ROS1-positive NSCLC
Everolimus	2016	Approval	Neuroendocrine tumors of gastrointestinal or lung origin
Palbociclib	2016	Approval for use in combination with fulvestrant	Advanced or metastatic breast cancer
Alectinib	2015	Accelerated approval	ALK-positive NSCLC
Trametinib	2015	Approval for use in combination with dabrafenib	Unresectable or metastatic melanoma with BRAF V600E or V600K mutations
Ixazomib	2015	Approval for use in combination with lenalidomide and dexamethasone	Multiple myeloma
Osimertinib	2015	Accelerated approval	EGFR T790M mutation-positive NSCLC
Cobimetinib	2015	Approval for use in combination with vemurafenib	Unresectable or metastatic melanoma with BRAF V600E or V600K mutation
Trifluridine/ tipiracil	2015	Approval	Metastatic colorectal cancer
Eltrombopag	2015	Approval	Thrombocytopenia in pediatric patients 1 year and older
Sonidegib	2015	Approval	Advanced basal cell carcinoma
Gefitinib	2015	Approval	NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
Panobinostat	2015	Accelerated approval for use in combination with bortezomib and dexamethasone	Multiple myeloma
Ibrutinib	2015	Approval	Waldenstrom’s macroglobulinemia
Olaparib	2014	Approval	Ovarian cancer with deleterious or suspected deleterious germline BRCA mutation
Ruxolitinib	2014	Approval	Polycythemia vera
Idelalisib	2014	Approval	Relapsed chronic lymphocytic leukemia (CLL)
Ceritinib	2014	Approval	ALK-positive NSCLC
Mercaptopurine	2014	Approval (oral suspension)	Acute lymphoblastic leukemia (ALL)
Sorafenib	2013	Approval	Differentiated thyroid cancer (DTC)
Afatinib	2013	Approval	The first-line treatment of NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
Lenalidomide	2013	Approval	Mantle cell lymphoma (MCL)
Dabrafenib	2013	Approval	Unresectable or metastatic melanoma with BRAF V600E mutation
Pomalidomide	2013	Accelerated approval	Multiple myeloma
Ponatinib	2012	Accelerated approval	Chronic myeloid leukemia (CML)
Abiraterone	2012	Expanded indication	Metastatic castration-resistant prostate cancer
Regorafenib	2012	Approval	Metastatic colorectal cancer
Bosutinib	2012	Approval	CML
Enzalutamide	2012	Approval	Prostate cancer
Pazopanib	2012	Approval	Soft tissue sarcoma (STS)
Imatinib	2012	Regular approval as adjuvant treatment	Complete gross resection of Kit (CD117) positive Gastrointestinal Stromal Tumors
Vismodegib	2012	Approval	Basal cell carcinoma
Axitinib	2012	Approval	RCC
Vemurafenib	2011	Approval	Unresectable or metastatic melanoma with the BRAF V600E mutation
Sunitinib	2011	Approval	Pancreatic neuroendocrine tumors
Vandetanib	2011	Approval	Medullary thyroid cancer
Dasatinib	2010	Accelerated approval	Chronic myeloid leukemia in chronic phase (CP-CML)
Nilotinib	2010	Accelerated approval	Philadelphia chromosome positive CP-CML
Lapatinib	2010	Accelerated approval for use in combination with letrozole	Hormone receptor positive metastatic breast cancer

As shown in Figure 1, 22 (50%) of the 44 oral oncology medications were approved to be administrated without restrictions on food intake. The effect of dosage timing in terms of pre-prandial versus post-prandial dosing on bioavailability was investigated in only 2 (9%) drugs, i.e. ibrutinib ⁷ and axitinib, ⁸ among them. For 14 (32%) drugs who were indicated to be given without food, studies on food timing were performed in only 5 (36%) of those, i.e. erlotinib, ⁹ abiraterone, ¹⁰ nilotinib, ¹¹ lapatinib, ¹² and sonidegib. ¹³ Comparative data of bioavailability in terms of peak plasma concentration and systemic drug exposure (i.e. area under the plasma concentration-time curve, AUC) under the recommended pre-prandial and post-prandial conditions from the literature are summarized in Table 1. OPEN IN VIEWER

For erlotinib ⁹ and nilotinib, ¹¹ peak plasma concentrations were increased by 33% and 44%, respectively, when administered 2 h after food compared with those administered at least 1 h before food. Likewise, systemic drug exposure (i.e., area under the plasma concentration-time curve, AUC) for the two drugs were slightly elevated by 15%–33% under 2-h post-prandial state than those under 1-h pre-prandial fasting state. For axitinib, ⁸ either peak plasma concentration or systemic drug exposure were slightly decreased by 35% or 29%, respectively, when administered 2 h after food relative to those administered at least 1 h before food. Similarly, on the basis of a population pharmacokinetic analysis, ¹³ the dosage timing in relation to food (i.e. 2-h post-prandial dosing versus at least 1-h pre-prandial dosing) did not have a statistically significant impact on sonidegib bioavailability. Accordingly, the differences in bioavailability of erlotinib, nilotinib, axitinib, and sonidegib between the recommended pre-prandial and post-prandial conditions appeared not to be of clinical relevance.

However, the bioavailability of lapatinib was substantially increased by 80%– 90% when taken 1 h before a low-fat meal compared to that under 1-h post-prandial conditions. ¹² Moreover, for ibrutinib ⁷ and abiraterone, ¹⁰ 4 to 10 times increases in peak plasma drug concentrations and 2 to 7 times increases in systemic drug exposure were observed when administered 2-h post a meal than that administrated at least 1 h prior to a meal. Similar to lapatinib, substantial differences in plasma concentrations of abiraterone and ibrutinib between pre-prandial and post-prandial dosing were seen even when they were given according to the labeling instruction for drug administration (Table 2). The impaired bioavailability of lapatinib, ibrutinib, and abiraterone, under the labeled post-prandial conditions might lead to compromised efficacy and even failure of anticancer treatment in some individual patients.

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Table 2.

Effect of dosage timing on peak concentration and systemic exposure of oral anticancer agents.

Medication	Dosage timing	Subjects (N)	Cmax (ng/ml) a	AUC (ng .h/ml) a	Cmax ratiob,c	AUC ratiob,c	Labeling recommendation on dosage timing d
Erlotinib 9	1-h pre-prandial (day 7)	NSCLC patients (23)	1830 ± 820	31010 ± 13720	1.44 (0.91−3.81)	1.33 (0.77, 2.49)	Taken at least 1 h before or 2 h after food
	2-h post-prandial (day 7)	NSCLC patients (23)	2640 ± 770	41530 ± 11290
Ibrutinib 7	Pre-prandial e	Healthy subjects (43)	38.5 ± 25.8	289 ± 163	3.85 (3.32, 4.46)	1.78 (1.63, 1.95)	Taken with or without food 14
	2-h post-prandial	Healthy subjects (43)	147 ± 100	521 ± 301
Abiraterone 10	Pre-prandial e	Healthy Caucasians (23)	92.2 ± 46.6	582 ± 317 f	10.21 (8.70, 11.97)	6.95 (6.02, 8.03)	Taken at least 2 h after food and no food should be eaten for at least 1 h post dosing.
	Pre-prandial e	Healthy Japanese (22)	128 ± 70.4	617 ± 218 g
	2-h post-prandial	Healthy Caucasians (23)	1006 ± 609	3801 ± 1889
	2-h post-prandial	Healthy Japanese (22)	1216 ± 604	4388 ± 1920
Axitinib 8	Pre-prandial e	Healthy subjects (18)	52.7 ± 7.9	206.8 ± 18.6	0.65	0.71	Taken with or without food.
	2-h post-prandial	Healthy subjects (12)	31.9 ± 8.6	138.0 ± 27.6
Nilotinib 11	Pre-prandial e	CML patients (44)	508 ± 175	14656 ± 5066	1.33 (1.18, 1.50)	1.15 (1.03, 1.28)	Taken at least 1 h before or 2 h after food
	2-h post-prandial	CML patients (24)	716 ± 286	19023 ± 7054
Lapatinib 12	1-h pre-prandial	Patients with solid tumors (12)	1290 ± 580	17500 ± 9450	1.90 (1.49−2.43)	1.80 (1.37−2.37)	Taken at least 1 h before or 1 h after food
	1-h post-prandial	Patients with solid tumors (12)	2520 ± 958	32700 ± 15369

Optimal instructions for dosage timing in relation to food could improve the balance of benefits against risks of anticancer treatment and patient compliance, which are crucial for oncological clinical practice. Unfortunately, as shown by the literature survey and labeling analysis, labeling information regarding dosage timing for several anticancer drugs, such as lapatinib, ibrutinib, and abiraterone, may not be optimum, leading to suboptimal bioavailability and plasma drug concentrations. This supports a call to regularly recalibrate the labeling information for dosage timing of oral anticancer medications in order to minimize the risks of compromised efficacy or unintended toxicities associated with suboptimal plasma drug concentrations. Also, when a remarkable food effect is observed, additional food–drug interaction studies evaluating the impact of drugs given at different time points before and after a meal should be conducted to ensure optimum dosing labeling.^15,16 Furthermore, oncologists should be aware of the potential suboptimal clinical outcome when different dosage timings with reference to food are implemented.