Results of a phase 1, randomized study evaluating the effects of food and diurnal variation on the pharmacokinetics of linifanib
Abstract
Purpose The primary objectives of this study were to evaluate the effect of food on the oral bioavailability and to evaluate the effect of diurnal variation on the pharma- cokinetics of linifanib, a novel tyrosine kinase (TK) inhibi- tor selective for vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, in patients with advanced solid tumors. Adverse events were monitored.
Methods This was a phase 1, open-label, randomized, crossover study. Thirty-four patients received dosing regi- mens to evaluate linifanib pharmacokinetic parameters under fasting and non-fasting conditions and with morn- ing or evening dosing. Adverse events (AEs) were assessed according to National Cancer Institute Common Terminol- ogy Criteria for AEs (Version 3.0).
Results The administration with food had a negligible clinical studies. The pattern of adverse advents reported in this study is similar to that seen in other studies of linifanib and other agents in the VEGF/PDGF TK receptor inhibitor class.
Keywords : TKIs · Diurnal variation · Food effect · PK · Bioavailability
Introduction
An oncogene often encodes a protein under tight control in order to properly facilitate cellular growth and prolif- eration. Many tyrosine kinase (TK) genes have long been identified as oncogenes, coding crucial signaling molecules that, when dysregulated, lead to cancer [1]. Rational drug design has led to the development of a number of different (24 %), hypertension (21 %), and palmar-plantar erythro- dysaesthesia syndrome (15 %).Conclusions Dosing with food or in the evening has a significant effect on the oral bioavailability of linifanib that should be taken into consideration when designing future target oncogenic TK signaling, through inhibition of either TK receptors or the enzymes themselves.
The TK signaling pathway involving vascular endothe- lial growth factor (VEGF) is one of the primary signaling pathways involved in angiogenesis [2]. The expression of this gene is under tight control, as evidenced by the lethal- ity of even a heterozygous knockout of VEGF [3]. Stud- ies have found that VEGF induces prosurvival signaling pathways in vascular endothelial cells and, conversely, that withdrawal of VEGF disrupts the formation of blood (PDGF) is another important proangiogenic factor. PDGF is a broad-spectrum growth factor that induces proliferation and motility in many cell types [6]. Both PDGF and VEGF have become primary targets in new cancer therapies, as their overexpression has been linked to cancerous prolif- eration and metastasis in a number of malignancies [7–11].
Linifanib (ABT-869) has been developed as a novel, tar- geted TKI with specificity for VEGF and PDGF receptors [12].One crucial aspect of drug development is establishing safe and effective dosing parameters for human trials. The bioavailability of a drug can significantly influence the abil- ity to access its desired target. For example, administering a drug with food may delay or reduce absorption, thereby potentially decreasing a drug’s activity when compared to administration without food [13]. Conversely, the presence of food may enhance absorption by increasing solubility, thereby increasing the bioavailability of a drug. Food may also affect the first-pass metabolism of a drug, increasing drug exposure [14]. Prolonged or excessive exposure to a drug can inhibit off target and potentially vital signaling pathways, thereby increasing the incidence or severity of adverse events [15]. Similar to the effect of food, diurnal variations in expression of gut transporter proteins, gastric pH, drug metabolizing enzymes, or kidney function can change the absorption, distribution, or clearance of many drugs [16–18].
For these reasons, the effects of different dosing parameters on the pharmacokinetics of many TKIs have been established; however, the bioavailability of these drugs varies widely by condition. Imatinib, an inhibitor of the break point cluster-Abelson TK fusion (BCR-Abl), has a bioavailability of 98 % irrespective of formulation, dosage range, or the presence of food [19, 20]. How- ever, nilotinib, another BCR-Abl inhibitor, has increased the bioavailability by 50–82 % when administered after a high-fat meal [21]. In addition, exposure of lapatinib, a HER2 and epidermal growth factor receptor inhibitor, increases by 325 % when coadministered with a high-fat meal [22].
Linifanib is a compound with low solubility and high permeability, which requires specific formulation technolo- gies to achieve sufficient bioavailability. Linifanib was for- mulated as Meltrex tablets for clinical studies. In order for linifanib to be administered appropriately in clinical trials, the effects of food and time of dosing on the PK and bio- availability of linifanib were investigated. Treatment-emer- gent adverse events were also concurrently monitored and reported.
Methods
Patients
Thirty-five adults with advanced or metastatic solid tumors and refractory to standard therapy were selected to partici- pate and 34 were randomized. Patients were required to have measurable or evaluable disease, Eastern Cooperative Oncology Group scores of 0–2, and acceptable hematol- ogy and chemistry values. The study was conducted at a single center in the United States in accordance with the protocol, International Conference on Harmonization (ICH) GCP guidelines, applicable regulations and guide- lines governing clinical study conduct and ethical princi- ples that have their origin in the Declaration of Helsinki. All patients gave their informed consent prior to participa- tion in the study.
Study design
This was a phase 1, single- and multiple-dose, open-label, randomized, crossover study. All subjects received 0.25 mg/ kg (maximum 17.5 mg) linifanib orally with 2.5 mg and/or 10 mg Meltrex tablets. Patients were randomly assigned to four sequences of linifanib regimens.In groups 1 and 2, patients were administered single morning doses under fasting and non-fasting conditions in a crossover scheme for periods 1 and 2 (Fig. 1). For morn- ing fasting conditions, patients were administered linifanib after a 10-h overnight fast. For morning non-fasting con- ditions, linifanib was administered 30 min after a high-fat (50 % calories from fat), 1,000-calorie meal. Patients were administered a single dose of linifanib, and pharmacoki- netic samples were taken at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12,24, 48, and 72 h post dose. In periods 3 and 4, patients were then administered daily doses, with dosing in the morning or in the evening in a crossover design (Fig. 1). For comparison of morning and evening dosing, linifanib was administered and pharmacokinetic samples were taken 0, 1, 2, 3, 4, 6, and 8 h post dose. For morning dos- ing, patients were administered linifanib after at least 10 h fasting. For evening dosing, patients were administered linifanib 2 h after their last meal and refrained from food for 2 h after dosing. At day 32, any active patient could begin an extension period. During this time, linifanib was continued as a single agent with evening doses until dis- ease progression or unacceptable toxicity prohibited fur- ther continuation.In groups 3 and 4, patients were administered single morning doses under fasting and non-fasting conditions in a crossover fashion for periods 1 and 2. Patients began the extension period at day 11 with a regimen of daily evening dosing under a fasting condition.
Pharmacokinetic and bioavailability assessments
Pharmacokinetic parameters of linifanib, including the maximum observed plasma concentration (Cmax), the time to Cmax (Tmax), and the area under the plasma concentra- tion–time curve (AUC) from time 0 to last measurable concentration (AUCt) were determined using non-compart- mental methods. For the single doses of days 1 and 7, the terminal phase rate constant and AUC from time 0 to infi- nite time (AUC ) were also determined. For multiple-dose pharmacokineti∞cs with morning or evening dosing, steady-state linifanib AUC (AUC24) was determined by assuming the linifanib concentration at 24 h post dose is the same as the measured predose (0-h) concentration within each subject.
To evaluate the effects of each condition, an analy- sis of variance (ANOVA) was performed for the natural logarithms of Cmax and AUC. The ANOVA had effects for condition (fasting or non-fasting, morning or evening),period of dosing, patient group, and patient nested within each group. The conditions were compared by a test with a significance level of 0.05. The bioavailability under each condition (fasting vs non-fasting, morning vs evening) was assessed, and 90 % confidence intervals were obtained for the Cmax and AUC.
Safety
Safety evaluations performed during this study included adverse event monitoring in conjunction with physical exams. Adverse events were summarized after coding using the Medical Dictionary for Regulatory Activities (MedDRA) Version 15.0, and their severities were assessed according to National Cancer Institute (NCI) Common Terminology Cri- teria for Adverse Events (CTCAE) Version 3.0.
Results
Patient demographics and disposition
Thirty-four out of 35 patients were randomized, 21 females and 13 males. Among them, 31 were white, 2 were black, and 1 was Asian. The median age was 58 years (range 36– 81). The median weight was 77 kg (range 52–156 kg). The most frequent reason for study discontinuation was disease progression (n = 21), accounting for 62 % of patients.
Pharmacokinetic results
A total of 25 patients had complete PK assessments for both period 1 and period 2 and were included in the non- fasting versus fasting analysis. A total of 16 patients in the morning fasting and 14 in the evening fasting condition were included in the diurnal analysis. The dose-normalized mean plus standard deviation (SD) of linifanib plasma con- centration–time profiles are represented in Fig. 2. The PK parameters of linifanib after a single oral dose in the morning under fasting or non-fasting conditions were determined (Table 1). ANOVA results demonstrated statistically significant effects for dose-normalized Cmax,AUC72, and AUC for non-fasting conditions as com- pared to fasting (p < 0.01). The PK parameters of linifanib after multiple oral doses administered in the morning or in the evening were also determined (Table 2). There was a statistically significant effect of evening dosing for Cmax (p < 0.01), but not for AUC24.
Bioavailability assessment for food effect and diurnal variation
Food appeared to have a negligible effect on dose-normal- ized linifanib AUC72 and AUC with no more than 18 % decrease in the point estimate of relative bioavailability (Table 3). The central value of the dose-normalized lini- fanib Cmax in the presence of a high-fat meal, however, was 60 % of that under fasting conditions.
Since the changes in Cmax due to food effect or from morning to evening dosing is outside the 80–125 % range that is commonly accepted as bioequivalence, the clini- cal relevance of the changes cannot be ruled out and must be further evaluated in the context of efficacy and safety data from clinical and preclinical studies [24]. Lower peak plasma concentration can be equally efficacious if the ther- apeutic window of a drug is large and a therapeutic affect can be achieved over a long period of time. In contrast, a high peak plasma concentration is needed for some drugs to have a maximal effect. Preclinical studies with linifanib have demonstrated that maximal inhibition of the receptor target was not necessary for effective tumor inhibition and that splitting a daily dose into two doses was statistically more effective [12]. For this reason, the decrease in peak plasma concentration may not affect the overall efficacy of linifanib if overall exposure remains the same.
Although no statistical analysis of adverse events as related to dosing regimen was done due to small number of subjects in the crossover design, the proportion of patients experiencing adverse events was generally similar among the treatment groups. The overall pattern of adverse events but no significant difference in overall exposure (AUC), suggesting that absorption is slower and over a longer win- dow in the non-fasting state. Consistent with this, the Tmax was increased numerically with food as compared to the fasting condition. A possible mechanism for lower plasma peak concentration after a high-fat meal is slower absorp- tion due to prolonged gastric emptying time in the presence of food. The Meltrex formulation that is an amorphous dis- persion formulation appears to have minimized the effect of food on linifanib AUC, which could have been signifi- cant for a compound with low solubility. Interestingly, the majority of TKIs whose bioavailability has been assessed have increased bioavailability or no change in bioavailabil- ity in the presence of food [23].
Similar to the effects of food on linifanib oral bioavail- ability, evening dosing led to a 36 % reduction in the peak plasma concentration and no significant change in overall exposure (AUC) when compared to morning dosing. This could be due to diurnal variations in the rate of absorption of linifanib. However, because the reduction is similar to a non-fasting state, it is also possible that 2-h fasting prior to dosing may not be sufficient to reduce the effect of food
reported in this study is similar to those seen in other studies of linifanib and other TKIs, including an increase in events of hypertension [25–28]. The rate of hypertension in this study was larger than what has been demonstrated in previous VEGF inhibitor studies; however, subsequent linifanib trials reported rates more consistent with previous studies [28, 29].
The results of this randomized, crossover study indi- cate that administration of linifanib in the presence of food or in the evening as compared to fasting, morning dosing can significantly affect its oral bioavailability. The clinical relevance of the effects remains to be evaluated. For this reason, morning fasting dosing was recommended for fur- ther trials. The safety profile of linifanib is consistent with studies using other TKIs and common treatment-emergent adverse events such as hypertension should be closely monitored and treated.