Effects of repeated oral doses of ketoconazole on a sequential ascending single oral dose of fedratinib in healthy subjects

Ken Ogasawara1 · Christine Xu2 · Vanaja Kanamaluru2 · Maria Palmisano1 · Gopal Krishna1

Abstract

Purpose Fedratinib is an orally administered Janus kinase 2-selective inhibitor that is indicated for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis in the United States. Fedratinib is metabolized by multiple cytochrome P450s (CYPs) in vitro, with the predominant contribution from CYP3A4. The primary objective of this study was to evaluate the effects of 14-day repeated 200 mg twice daily (BID) oral doses of a strong CYP3A4 inhibitor, ketoconazole, on a sequential ascending single oral dose of fedratinib in healthy male subjects.
Methods An open-label, fixed-sequence, two-treatment cross-over study was conducted. Two cohorts of healthy adult males received two single doses of fedratinib (50 mg in Cohort 1 and 300 mg in Cohort 2) with one dose administered alone on Day 1 of Period 1 and the other dose coadministered with ketoconazole in the morning of Day 6 of Period 2. Subjects in both cohorts received 200-mg BID (Days 1–14) ketoconazole during Period 2.
Results Coadministration of repeated 200-mg BID oral doses of ketoconazole for 14 days increased fedratinib exposure by 3.85- and 3.06-fold for area under the plasma concentration–time curve from time zero to infinity following a single oral dose of fedratinib of 50 and 300 mg, respectively. Oral administration of a single dose of 50 or 300 mg of fedratinib, administered alone or coadministered with steady-state ketoconazole, was safe and tolerable in the healthy male subjects. Conclusions These results serve as the basis for fedratinib dose reduction when fedratinib is coadministered with strong CYP3A4 inhibitors.

Keywords Fedratinib · CYP3A4 · Drug–drug interaction · Ketoconazole · Pharmacokinetics

Introduction

Fedratinib is an oral kinase inhibitor with activity against wild-type and mutationally activated Janus kinase (JAK) 2 and FMS-like tyrosine kinase 3 (FLT3). JAK/signal transducer and activation of transcription (STAT) pathway plays a central role in cytokine receptor signaling, and the association of dysregulated JAK/STAT pathway with hematological malignancies and autoimmune diseases has been suggested [1–3]. For example, mutations in JAK2 and Calreticulin genes are associated with specific alterations of the immune system in myelofibrosis (MF) [4]. Fedratinib was approved in Aug 2019 for the treatment of adult patients with intermediate-2 or high-risk MF by the US Food and Drug Administration (FDA) [5].
Pharmacokinetics (PK) of fedratinib has been characterized in both patients with MF [6–8] and healthy subjects [9, 10]. The approved dose of fedratinib is 400 mg once daily [5], and fedratinib exposure increased in an approximately dose-proportional manner over dose range of 300–500 mg at steady state [8]. The maximum tolerated dose of fedratinib was determined at 680 mg in patients with MF [7], and single oral doses of up to 680-mg fedratinib were tolerated by the healthy subjects [10]. Fedratinib has a large apparent volume of distribution at steady state (1770 L) indicating extensive tissue distribution, and it is eliminated in a bi-phasic manner with an effective half-life of accumulation(t1/2,eff) of 41 h and terminal elimination half-life (t1/2,z) of approximately 114 h in patients with MF [5].
Patients frequently use more than one medication at a time, and it is important to evaluate potential drug–drug interactions (DDIs) which can lead to changed systemic exposure, resulting in variations in drug response of the coadministered drugs [11]. Cytochrome P450 (CYP) 3A4 is the most abundant human CYP enzyme contributing to the metabolism of approximately half the drugs [12], and thus, it plays a significant role in many DDIs. Fedratinib is metabolized by multiple CYPs in vitro, with a predominant contribution from CYP3A4 [5]. Therefore, the present clinical pharmacology study was conducted to assess the effect of CYP3A4 inhibition mediated by a strong CYP3A4 inhibitor (ketoconazole) on fedratinib PK in healthy subjects. Thus, the primary objective of this study was to assess the effect of 14-day repeated 200-mg twice daily (BID) oral doses of ketoconazole on fedratinib PK. The secondary objective was to assess safety and tolerability of a sequential ascending single oral dose of fedratinib coadministered with ketoconazole.

Methods

Study and ethical consideration

This was a single center, open-label, fixed-sequence, nonrandomized, two-period, two-treatment, two-cohort study with a sequential ascending single oral dose of fedratinib coadministered with ketoconazole. This study was conducted at the Covance Dallas Clinical Research Unit (Dallas, TX). The protocol and its amendment were submitted to an Institutional Review Board (Independent Review Board, Inc., Plantation, FL) for review and written approval. The protocol complied with recommendations of the 18th World Health Congress (Helsinki, 1964) and all applicable amendments. The protocol also complied with the laws and regulations, as well as any applicable guidelines of the USA, the country where the study was conducted. Informed consent was obtained at screening, prior to the conduct of any studyrelated procedures.

Study population

Healthy male subjects who were between 18 and 55 years of age, and who had a body mass index (BMI) between 18 and 30 kg/m2 were eligible for this study. Subjects were certified as healthy by a clinical assessment, with supine systolic blood pressure (SBP) > 95 and < 140 mmHg, supine diastolic blood pressure (DBP) > 45 and < 90 mmHg, heart rate (HR) > 40 and < 100 beats per minute, and normal standard 12-lead electrocardiograms (ECG) at screening. Exclusion criteria included history of clinically relevant disease, history of drug or alcohol abuse, recurrent nausea and/or vomiting (more than twice a month), any contraindications to ketoconazole, and any consumption of citrus (such as grapefruit, orange) or their juices within 5 days before inclusion.

Study design and treatment

This was an open-label, two-treatment, fixed sequence study with a 15-day washout between doses of fedratinib and 10 days between the first dose of fedratinib and the first dose of ketoconazole, conducted in two sequential cohorts (Fig. 1). The study duration for each subject consisted of two periods for a total of up to 35 days (not including screening) and included: Screening (28–2 days before inclusion); Period 1: 10 days (confined at the clinical research unit from Day-1 to Day 3 of the period); Washout: 10 days between administration of fedratinib in Period 1 and first administration of ketoconazole in Period 2, and 15 days between each administration of fedratinib; Period 2: 15 days (confined at the clinical research unit from Day-1 to Day 15 of the period); and end-of-study visit: 7–10 days after the last dose of ketoconazole.
Each cohort of healthy adult males (7 subjects per cohort) received a single dose of fedratinib (50 mg for Cohort 1 and 300 mg for Cohort 2), with one dose administered alone on Day 1 of Period 1 and the other dose coadministered with ketoconazole in the morning of Day 6 of Period 2, with 240 mL of noncarbonated water following a fast of at least 10 h overnight. Food was not allowed for at least 4 h after fedratinib administration. Water was allowed except for 1 h after receiving study drugs. Subjects in both cohorts received twice daily (BID) doses of 200-mg ketoconazole with noncarbonated water from Days 1 to 14 during Period 2. Ketoconazole doses were administered in the fed state, except on the morning of Day 6 when coadministered with fedratinib in the fasted state.

Pharmacokinetic sampling times and bioanalytical methods

Blood samples for measurement of plasma fedratinib concentrations were collected at predose and 0.5-, 1-, 1.5-, 2-, 3-, 4-, 6-, 8-, 12-, 24-, 48-, 72-, 96-, 120-, 168-, and 216-h postdose of fedratinib. Concentrations of fedratinib in plasma were measured using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay with lower limit of quantification (LLOQ) of 1 ng/mL and calibration range of 1–1000 ng/mL [6]. Plasma samples for measurement of ketoconazole were collected at predose and 1, 2, 3, 4, 6, 8, and 12 h postdose of ketoconazole on Day 6 of Period 2. Concentrations of ketoconazole in plasma were measured using a validated LC–MS/MS assay with LLOQ of 5 ng/mL, calibration range of 5–1000 ng/mL and good accuracy (− 8.6 to 5.6%) and precision (2.9–7.7%).

Pharmacokinetic variables

Plasma concentrations of fedratinib and ketoconazole and relative actual time values were used to calculate the PK parameters using noncompartmental methods with validated software (WinNonlin Professional, Version 5.2.1, Pharsight). The PK parameters for fedratinib were maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration–time curve (AUC) from time zero to infinity (AUC 0–inf), AUC from time zero to the last time point with a measurable plasma concentration (AUC 0–t), t1/2,z, t1/2,eff, apparent clearance (CL/F), and apparent volume of distribution at steady state (VSS/F). Effective half-life was calculated based on AUC 0–inf and AUC from time 0 to 24 h [13]. AUC 0–inf values with more than 30% of area extrapolation (and associated t1/2,eff, CL/F, and VSS/F values) were not reported. The PK parameters for ketoconazole were Cmax, tmax, observed predose plasma concentration before treatment administration during repeated dosing (Ctrough), and AUC over the dosing interval (12 h; AUC 0–12).

Statistical considerations

Sample size was determined based on the preliminary PK results for 80–680-mg cohorts from an ascending singledose study in healthy subjects [10]. The total-subject variance was calculated for both AUC 0–inf and Cmax. Assuming the within-subject variance is equal to one-half of the totalsubject variance, the within-subject standard deviation (SD) was approximated as 0.25 and 0.27 for AUC 0–inf and Cmax, respectively. With a total of six subjects and a true withinsubject SD of 0.25, the ratio of adjusted geometric means was estimated with a maximum imprecision of 32.7% with 90% assurance.
Pharmacokinetic parameters were analyzed using a linear mixed-effects model for log-transformed fedratinib Cmax, AUC 0–inf, and AUC 0–t for each cohort. Estimate and 90% confidence intervals (CIs) for the geometric means ratio of fedratinib coadministered with ketoconazole vs. fedratinib alone were provided for fedratinib Cmax, AUC 0–inf, and AUC 0–t.

Safety assessment

Subjects were monitored for safety and tolerability via adverse events (AEs) spontaneously reported by subjects or observed by the investigator, physical examination, body weight, oral body temperature, vital sign assessments (HR, SBP, and DBP, and 12-lead ECG), and clinical laboratory tests (hematology, coagulation, serum biochemistry, and urinalysis). Clinically significant abnormalities, if any, were to be monitored until resolution or until clinically stable.

Results

Study subjects

A total of 14 subjects were enrolled in this study; 7 each in Cohort 1 and Cohort 2, respectively. All 14 subjects completed the study as planned. Demographic characteristics at baseline are presented in Table 1. Of these 14 subjects, 9 were White and 5 were Black or African American. The mean age and body mass index were similar for each cohort. Effect of ketoconazole on fedratinib PK
Mean fedratinib plasma concentration–time profiles from a single oral dose of 50- or 300-mg fedratinib when administered alone and when administered with ketoconazole are shown in Fig. 2. Fedratinib plasma concentrations in descending phase appeared to decline in a bi-phasic manner. The peak fedratinib concentrations were attained at a median tmax of 1.5 and 3 h for 50- and 300-mg fedratinib, respectively, and were not significantly affected by coadministration with ketoconazole. The plasma fedratinib PK parameters when administered alone and when administered with ketoconazole are summarized in Table 2, and treatment ratio estimates are presented in Table 3. Coadministration of repeated 200 mg BID oral doses of ketoconazole for 14 days to healthy male subjects increased fedratinib exposure by 1.85-fold (90% CI 1.62–2.11) and 1.93-fold (90% CI 1.18–3.17) for Cmax; by 3.64-fold (90% CI 3.20–4.13) and 3.20-fold (90% CI 2.51–4.09) for AUC 0-t; by 3.85-fold (90% CI 2.89–5.12) and 3.06-fold (90% CI 2.46–3.80) for AUC 0–inf after a single oral dose of fedratinib of 50 and 300 mg, respectively. The effective half-life of fedratinib was prolonged by coadministration of ketoconazole (by 49% and 65% for 50 and 300 mg, respectively), while the terminal elimination half-life of fedratinib did not significantly change in the presence or absence of ketoconazole.
The plasma ketoconazole PK parameters are summarized in Table 4. Ketoconazole Ctrough after 5-day repeated 200-mg BID oral doses of ketoconazole was in the range expected to provide significant inhibition of CYP3A4 [14].

Safety

There were no serious or severe treatment-emergent AEs (TEAEs) during this study. One subject in Cohort 1 experienced 4 TEAEs (2 following administration of 50-mg fedratinib alone, 1 following administration of ketoconazole alone, and 1 following coadministration of ketoconazole and fedratinib), none of which were considered by the investigator to be related to fedratinib treatment and 2 of which (headache and night sweat) were considered to be related to ketoconazole administration.
There were no TEAEs reported for Cohort 2 following administration of ketoconazole alone. Five subjects in Cohort 2 receiving fedratinib together with ketoconazole experienced TEAEs. One subject had mild elevation in lipase levels at screening (> 2 × upper limit of normal or ULN) and on Period 2, Day 11 (> 3 × ULN) that was resolved prior to the end-of-study visit. Other TEAEs were all mild and included 2 TEAEs of nausea, 1 of vomiting, 1 of diarrhea, and 1 of dizziness. Overall, all TEAEs reported during this study were mild in severity, except for 1 moderate TEAE of vomiting. All TEAEs were resolved prior to study completion. There were no clinically meaningful potentially clinically significant abnormalities or clinically meaningful changes or trends for any clinical laboratory test, vital sign, or ECG parameters.

Discussion

Coadministration of repeated 200-mg BID oral doses of ketoconazole for 14 days to healthy male subjects increased fedratinib AUC 0–inf by 3.85- and 3.06-fold after a single oral dose of fedratinib of 50 mg and 300 mg, respectively, which further confirmed that fedratinib is a substrate of CYP3A4. Oral administration of a single dose of 50 or 300 mg of fedratinib, administered alone or coadministered with steadystate ketoconazole, was safe and tolerable in the healthy male subjects in this study. These results suggest that strong CYP3A4 inhibitors that increase fedratinib plasma concentrations need to be used with caution. In place of a strong CYP3A4 inhibitor, alternative therapies that do not strongly inhibit CYP3A4 activity should be considered when coadministering with fedratinib. If alternative therapies that do not strongly inhibit CYP3A4 are not available, fedratinib dose should be reduced when coadministering with a strong CYP3A4 inhibitor. Similar to a need for fedratinib dose reduction when taken with a strong CYP3A4 inhibitor, the dose of only other approved MF therapy, ruxolitinib, also needs to be reduced when ruxolitinib is taken with a strong CYP3A4 inhibitor [15]. However, while fedratinib dose reduction, when taken with strong CYP3A4 inhibitors, is not dependent on patient’s platelet counts [5], ruxolitinib dose reduction, when taken with strong CYP3A4 inhibitor, is dependent on platelet counts [15].
Fedratinib exhibited a greater than dose-proportional increase in exposure across a wide dose range in a Phase 1 dose-escalation study in patients with MF (30–800 mg) [7] and in an ascending single-dose study in healthy subjects (10–680 mg) [10]. Because of the uncertainty of a DDI effect with nonlinear PK of fedratinib observed in the Phase 1 dose-escalation studies, a two-step approach was used in this DDI study to mitigate the risk of an unexpectedly large increase in exposure in healthy subjects under the interaction conditions. Two different cohorts of subjects were given sequential ascending doses of fedratinib (50 and 300 mg). Based on the preliminary PK profile and safety data from Cohort 1 following administration of a single 50-mg dose of fedratinib with repeated 200-mg BID oral doses of ketoconazole, the predicted fedratinib exposure at 300 mg with coadministration of ketoconazole (approximately threefold increase) was determined to be similar to the exposure of a single 500-mg dose of fedratinib. Therefore, a decision was made to proceed to Cohort 2, with single doses of 300-mg fedratinib. A subsequent population PK analysis indicated that fedratinib exhibits linear and time-invariant PK at doses of 200 mg and above and that the finding of more than doseproportional increase of fedratinib exposure across a wider dose range could be explained by larger distribution and/ or elimination clearance at lower doses (below 120 mg), which were not studied beyond Phase 2 studies [6]. Thus, the extent of interaction obtained with ketoconazole in the current study would also hold true at the therapeutic dose of fedratinib (400 mg).

Ketoconazole is a well-known strong CYP3A4 inhibitor.

It has been widely used as a reference inhibitor in clinical DDI study to evaluate the potential effect of CYP3A4 inhibition on substrate drugs for CYP3A4. In 2013, FDA limited the usage of ketoconazole due to the risk of fatal liver injury, adrenal insufficiency, and DDI [16, 17]. The European Medicines Agency’s Committee on Medicinal Products for Human Use also recommended in 2013 that the marketing authorizations of oral ketoconazole-containing medicines should be suspended throughout the European Union [18].
AUC 0-inf area under the plasma concentration–time curve from time zero to infinity, AUC 0-t area under the plasma concentration–time curve from time zero to the last time point with a measurable plasma concentration, BID twice daily, CI confidence interval, Cmax maximum observed plasma concentration
This DDI study was conducted before these recommendations (between August 3, 2012 and November 26, 2012), and no AEs related to liver injury or adrenal insufficiency were reported in this study. Ketoconazole administered as 200 mg BID by oral route was selected based on the PK characteristics (a long-terminal half-life) of fedratinib. Maintaining ketoconazole exposure over the PK profile of substrate is critical as the half-life of the substrate relative to that of ketoconazole becomes longer. For these substrates, 200-mg BID ketoconazole results in a higher degree of inhibition by providing more sustained CYP3A inhibition than 400-mg QD [19]. Therefore, ketoconazole was given BID for 5 days in the current study to reach steady state with maximum inhibitory effect prior to fedratinib administration. After coadministration of a single dose of fedratinib on Day 6, ketoconazole was given continuously until Day 14, to maintain the inhibitory effect during the prolonged elimination phase of fedratinib.
Coadministration of ketoconazole increased fedratinib Cmax by approximately 1.9-fold, which could in part be explained by inhibition of first-pass effect and metabolism before fedratinib attains peak plasma concentration. Ketoconazole should also reduce elimination of fedratinib; however, no apparent difference in terminal elimination half-life of fedratinib was observed in the presence or absence of ketoconazole. The most likely explanation is that the terminal phase of fedratinib reflects redistribution and not elimination, which is supported by fedratinib population PK model in patients with MF, polycythemia vera, and essential thrombocythemia (two-compartment model with large peripheral volume of distribution) [6].
AUC 0-12 area under the plasma concentration–time curve over the dosing interval (12 h), AUC 0-t area under the plasma concentration– time curve from time zero to the last time point with a measurable plasma concentration, Cmax maximum observed plasma concentration, Ctrough observed predose plasma concentration before treatment administration during repeated dosing, CV% percent coefficient of variation, N number of subjects, tmax time to maximum observed plasma concentration a Median (min, max) b One subject was excluded from PK population due to vomiting around 1 h postdose
The increase in AUC with ketoconazole in this study is generally in line with that expected based on the extent of metabolism of fedratinib by CYP3A4 in vitro. Consistent with this increase in exposure, effective half-life of fedratinib was prolonged by coadministration of ketoconazole, which might be more appropriate indicator of fedratinib elimination. A 15-day washout period was used in this study and is shorter than five times terminal elimination half-life of fedratinib (approximately 24 days). All predose plasma fedratinib samples in Period 2 were above the LLOQ for fedratinib but were all less than 5% of Cmax. which supported the 15-day washout period in this study. This discrepancy might be because the terminal phase of fedratinib reflects redistribution and not elimination.
In summary, the current DDI study with a strong CYP3A4 inhibitor, ketoconazole, showed a clinically significant threefold increase in fedratinib exposure following a single 300-mg dose of fedratinib in healthy subjects. These results serve as the basis for fedratinib dose reduction when coadministering fedratinib with strong CYP3A4 inhibitors.

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