
==== Front
Clin Transl Sci
Clin Transl Sci
10.1111/(ISSN)1752-8062
CTS
Clinical and Translational Science
1752-8054
1752-8062
John Wiley and Sons Inc. Hoboken

10.1111/cts.70028
CTS70028
CTS-2024-0263
Article
Article
Drug–drug interactions of icenticaftor (QBW251) with a 5‐probe cytochrome P450 cocktail and oral contraceptives
Icenticaftor (QBW251) drug‐drug interactions
Huth et al.
Huth Felix https://orcid.org/0000-0002-7121-4394
1 felix.huth@novartis.com

Glaenzel Ulrike 1
Drollmann Anton 1
Weis Wendy 2
Zack Julia 2
Bebrevska Lidiya 1
1 Novartis Pharma AG Basel Switzerland
2 Novartis Pharmaceuticals Corporation East Hanover New Jersey USA
* Correspondence
Felix Huth, Novartis Pharma AG, BioMedical Research, Postfach, Basel CH‐4002, Switzerland.
Email: felix.huth@novartis.com

17 9 2024
9 2024
17 9 10.1111/cts.v17.9 e7002823 8 2024
14 5 2024
04 9 2024
© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Abstract

A drug–drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor (QBW251) on the pharmacokinetics (PK) of a 5‐probe cytochrome P450 (CYP) substrate cocktail, guided by in vitro studies in human hepatocytes and liver microsomes. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. The static‐mechanistic DDI assessment indicated that icenticaftor may moderately induce the metabolic clearance of co‐medications metabolized by CYP3A4 (area under the concentration–time curve [AUC] ratio: 0.47) and potentially CYP2C; icenticaftor may also weakly inhibit the metabolic clearance of co‐medications metabolized by CYP1A2 and CYP3A4 (AUC ratio: 1.35 and 1.86, respectively) and moderately inhibit CYP2B6 (AUC ratio: 2.11). In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 (AUC ratio: 3.35) and CYP2C19 (AUC ratio: 2.70). As expected from the results of the in vitro studies, weak induction was observed for CYP3A4 (AUC ratio: 0.51) and CYP2C8 (AUC ratio: 0.66). In the OC DDI study, co‐administration of icenticaftor 450 mg b.i.d. with monophasic OC containing 30‐μg EE and 150‐μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle‐stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or patients using OCs.

Novartis Pharma AG source-schema-version-number2.0
cover-dateSeptember 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:17.09.2024
Huth F , Glaenzel U , Drollmann A , Weis W , Zack J , Bebrevska L . Drug–drug interactions of icenticaftor (QBW251) with a 5‐probe cytochrome P450 cocktail and oral contraceptives. Clin Transl Sci. 2024;17 :e70028. doi:10.1111/cts.70028
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pmc Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Icenticaftor is an orally administered cystic fibrosis transmembrane conductance regulator potentiator that may be useful for the treatment of patients with chronic obstructive pulmonary disease and chronic bronchitis. WHAT QUESTION DID THIS STUDY ADDRESS?

This study explored the drug–drug interactions of icenticaftor with cytochrome P450 (CYP) substrates and oral contraceptives (OCs). WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Data from the drug–drug interaction studies indicated that icenticaftor may induce the metabolic clearance of some co‐medications (those metabolized by CYP2C8 and CYP3A4) and may also inhibit the metabolic clearance of co‐medications metabolized by CYP2B6. For the CYP1A2 and CYP2C19 substrates caffeine and omeprazole, respectively, moderate inhibition by icenticaftor was observed clinically, although this was not indicated by the static‐mechanistic DDI model using in vitro data. OCs may not be effective when co‐administered with icenticaftor. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These data inform the safe use of icenticaftor in patients who use concomitant medications such as substrates of CYP enzymes or OCs. They will also aid label development and patient selection for upcoming icenticaftor clinical trials.

INTRODUCTION

Icenticaftor (QBW251) is an orally administered cystic fibrosis transmembrane conductance regulator (CFTR) potentiator targeted to increase the activity of mutated/defective CFTR residing in the cell membrane; it is currently in development as add‐on therapy for the treatment of chronic obstructive pulmonary disease (COPD) and chronic bronchitis. 1 , 2 In a 4‐week Phase II proof‐of‐concept study, icenticaftor demonstrated improvements in respiratory function compared with placebo. 1 A 24‐week Phase IIb dose‐finding study also demonstrated improvements in trough forced expiratory volume in 1 s (FEV1), cough, sputum, and rescue medication use as well as reduction in fibrinogen levels. 2

Icenticaftor showed rapid absorption, consistent with its high apparent permeability and a terminal half‐life (T 1/2) of 10–13 h in healthy subjects; additionally, its plasma exposure increased over‐proportionally with dose. 3 At its therapeutic dose of 300 mg twice daily (b.i.d.), its maximum observed drug concentration (C max) and area under the concentration–time curve (AUC) from time zero to 24 h were 1640 ng/mL and 6840 ng*h/mL, respectively, at Day 14 in patients with COPD (data on file). When co‐administered with a high‐fat meal, the icenticaftor C max and AUC were increased by 26% and 49%, respectively (data on file). Icenticaftor is predominantly cleared by metabolism via glucuronidation, mainly due to the uridine diphosphate glucuronosyltransferase (UGT) enzyme UGT1A9, with less contribution by UGT2B7 and the oxidative cytochrome P450 (CYP) enzymes CYP3A4 and CYP1A2. Icenticaftor is not a substrate of typical drug transporters and was not indicated to inhibit drug transporters based on a static drug–drug interaction (DDI) assessment, except for intestinal breast cancer resistance protein. Results from two Phase I clinical DDI studies evaluating the effect of concomitant medications on the pharmacokinetics (PK) of icenticaftor, guided by in vitro inhibition and induction studies, are reported here. One DDI study investigated the effect of icenticaftor on the PK of CYP enzyme substrates in healthy male and female subjects. Another DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. A physiologically based pharmacokinetic (PBPK) model, constructed based on data from physicochemical, preclinical, and clinical studies, was established and applied to predict the DDIs of icenticaftor as a victim and as a perpetrator.

METHODS

Preclinical in vitro studies

Preclinical studies were conducted to evaluate the potential of icenticaftor to induce drug‐metabolizing enzymes in human hepatocytes (Methods S1) and to assess CYP enzyme inhibition by icenticaftor (Methods S2) as well as the icenticaftor metabolite CKW231 (M8) in human liver microsomes (Methods S3).

Static‐mechanistic DDI assessment of icenticaftor as a perpetrator of CYP enzymes

As recommended by the US Food and Drug Administration (FDA), a static‐mechanistic DDI assessment for CYP enzymes, based on the in vitro DDI parameters, was performed for icenticaftor at steady state for 300 mg twice daily (b.i.d.). 4

Clinical DDI studies

Two DDI studies were conducted in accordance with ethical principles consistent with the International Conference on Harmonization Good Clinical Practice guideline E6. The protocol and any amendments were reviewed by the institutional review board or independent ethics committee at each site. All subjects provided written informed consent.

CYP substrate cocktail study

Study objectives

The primary objective was to evaluate the effect of multiple doses of icenticaftor on the single‐dose PK of caffeine (CYP1A2 substrate), midazolam (CYP3A substrate), repaglinide (CYP2C8 substrate), S‐warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate) in healthy subjects. The safety and tolerability of multiple doses of icenticaftor when co‐administered with the CYP substrates were also assessed.

Study design and treatments

In this open‐label, fixed‐sequence, two‐period Phase I study in healthy subjects, caffeine, midazolam, repaglinide, S‐warfarin, and omeprazole were administered as a single‐dose 5‐probe cocktail. The cocktail approach to assessing potential DDIs is supported by the FDA and European Medicines Agency (EMA) guidelines. 4 , 5

The study consisted of a 28‐day screening period, two baseline evaluations (one before each treatment period), and two treatment periods (Figure 1). In Treatment Period 1, subjects received a single oral dose of the 5‐probe cocktail on Day 1 (Treatment A), followed by serial PK sampling for up to 168 h postdose. The 5‐probe cocktail contained caffeine 100 mg (one 100 mg tablet), midazolam 5 mg (2.5 mL of 2 mg/mL syrup), repaglinide 1 mg (one 1 mg tablet), S‐warfarin 4 mg (one 4 mg tablet), and omeprazole 20 mg (one 20‐mg delayed‐release capsule). Subjects received the 5‐probe cocktail with approximately 240 mL of water on Day 1 after at least 10 h of fasting before dosing and continued to fast for 4 h postdose. All 5‐probe substrates were administered within approximately 5 min, with a 14‐day washout period following dosing in Treatment Period 1 and the first dose of icenticaftor in Treatment Period 2.

FIGURE 1 CYP substrate cocktail study design. An open‐label, fixed‐sequence, two‐period, Phase I study conducted to evaluate the effect of multiple doses of icenticaftor on the single‐dose PK of caffeine, midazolam, repaglinide, S‐warfarin, and omeprazole. aThere was a 14‐day washout period between dosing in Treatment Period 1 and the first dose of icenticaftor in Treatment Period 2. bAll subjects were contacted (telephone/email) approximately 30 days after the last dose of study treatment(s). The baseline safety assessment for Treatment Period 1 was the day before patients received a single dose of the 5‐probe cocktail. The baseline for Treatment Period 2 was the day before patients received 300 mg icenticaftor b.i.d., which occurred after a 14‐day washout period following dosing in Treatment Period 1. b.i.d., twice daily; CYP, cytochrome P450; EOS, end of study; PK, pharmacokinetics.

In Treatment Period 2, subjects received Treatment B, which consisted of 300 mg oral icenticaftor (one 300 mg tablet b.i.d.) for 15 days (Days 1 through 15), with a single oral dose of the 5‐probe cocktail co‐administered with the morning icenticaftor dose on Day 9. Serial PK sampling for the cocktail drugs was performed on Day 9 for up to 168 h postdose. Blood samples for icenticaftor PK were collected on Days 1, 4, 7, 9, 13, and 15 before and 3 h after icenticaftor morning administration. Subjects received icenticaftor b.i.d. under the same conditions as those for the 5‐probe cocktail. Before the morning dose on Day 9, subjects fasted for at least 10 h and continued to fast for at least 4 h postdose. For all other morning and evening doses, subjects fasted for at least 1 h before dosing and remained fasted for at least 2 h postdose. Subjects received the 5‐probe cocktail in the same manner as that in Treatment Period 1. The preferred order for administration of the study treatment was icenticaftor first, followed by all 5‐probe substrates within approximately 5 min.

Icenticaftor was manufactured by Novartis Pharma AG (Basel, Switzerland) and supplied by Fisher Clinical Services (Allschwil, Switzerland). All other investigational products were supplied by Celerion (Arizona, USA).

Subjects

Healthy male and female (of nonchildbearing potential) subjects aged 18–55 years, with a body mass index (BMI) of 18.0–29.9 kg/m2 and body weight ≥50 kg, were eligible for inclusion in the study. Key exclusion criteria are described in Methods S4.

Assessments

The following PK parameters were determined from the plasma concentration–time data for all five substrates, using the actual recorded sampling times and noncompartmental methods (Phoenix® WinNonlin® Version 8.1, Certara, Princeton, NJ, USA): C max, time to reach maximum (peak) drug concentration (T max), area under the concentration–time curve from time zero to the last measurable concentration sampling time (AUClast), area under the concentration–time curve from time zero to infinity (AUCinf), percent of AUCinf extrapolated (AUC%extrap), T 1/2, terminal elimination rate constant (λz), apparent total body clearance of drug from plasma following extravascular administration (CL/F), and apparent volume of distribution following extravascular administration (Vz/F). The drug concentration observed at 3 h postdose (C3) and the trough (predose) drug concentration observed at the end of the dosing interval (C trough) were determined only for icenticaftor (Methods S4).

Safety assessments included adverse event (AE) and serious AE (SAE) monitoring as well as physical examinations, vital signs measurement (pulse rate, blood pressure, height, and weight), clinical laboratory evaluations (hematology, blood chemistry, urinalysis, coagulation, hepatitis, and HIV markers), electrocardiogram, Richmond Agitation‐Sedation Scale (RASS), pulse oximetry, and blood glucose monitoring.

Statistical analysis

For C max, AUCinf, and AUClast of each probe substrate, a linear mixed‐effects model was fitted to the natural log‐transformed PK parameters to estimate the effect of icenticaftor on probe substrates, with treatment as a fixed effect and subject as a random effect. Probe substrate plus icenticaftor was the test treatment (Treatment B) and probe substrate alone was the reference treatment (Treatment A). For each comparison, a point estimate and the corresponding two‐sided 90% confidence interval (CI) for the difference between the means of the test and reference treatments (test − reference) were calculated. The values were anti‐log transformed to obtain the geometric mean ratio and its 90% CI for test versus reference on the original scale. Descriptive statistics are provided for other parameters.

OC study

Study objectives

The primary objective was to assess the effect of icenticaftor on the PK of a monophasic combined OC containing EE and LVG. The PK, PD, and safety of icenticaftor were also assessed.

Study design and treatments

This was a confirmatory, open‐label, single‐sequence, two‐treatment period, Phase I study in healthy premenopausal females conducted at two centers (Figure 2). The study consisted of a 28‐day screening period and a synchronization period of up to three cycles, followed by Treatment Period 1 (Days 1–21 inclusive), where subjects received monophasic OC containing 30‐μg EE and 150‐μg LVG once daily (o.d.) for 21 days. During this period, subjects attended the clinic daily for dosing and had each dose within ±2 h of their reference dosing time. An OC pill‐free period was maintained on Days 22–28. In Treatment Period 2 (Days 29–49 inclusive), icenticaftor 450 mg b.i.d. was administered in combination with OC for 21 days. A final pill‐free period (Days 50–56 inclusive) was maintained before the safety follow‐up period (Days 57–70) and end‐of‐study evaluation.

FIGURE 2 OC study design. A confirmatory, open‐label, single‐sequence, two‐treatment period, Phase I study to assess the effect of icenticaftor on the PK of a monophasic combined OC. aSynchronization occurred after screening and before Baseline 1, if required. bWashout period of 7 days between Treatment Periods 1 and 2. cBaseline 2 was on Day 28 of the study. The baseline safety assessment for Treatment Period 1 was the day before patients received OC. The baseline for Treatment Period 2 was on the day before patients received OC + icenticaftor 450 mg b.i.d., which occurred after a 7‐day washout period following dosing in Treatment Period 1. EOS, end of study; OC, oral contraceptive; PK, pharmacokinetics.

If a synchronization period was required, monophasic OC was self‐administered by the subject for three cycles in accordance with the label. The dosing time on Day 1 was defined as the reference time for Treatment Period 1. Subsequent doses in Treatment Period 1 (Days 2–21) were administered at this reference time (±2 h). Icenticaftor was administered in the morning and evening, and OC was administered in the morning. The dosing time on the morning of Day 29 was defined as the reference time for Treatment Period 2. Subsequent morning doses of OC and icenticaftor (Days 30–49) were administered at this reference time (±2 h). The reference time for evening doses of icenticaftor was defined as the morning reference time + 12 h. Subsequent evening doses in Treatment Period 2 (Days 30–49) were administered at the evening reference time (±2 h). All doses were administered with approximately 240 mL of water.

Icenticaftor (25‐ and 100‐mg capsules) was prepared by Novartis and supplied as an open‐label bulk medication. Monophasic OC containing 30‐μg EE and 150‐μg LVG was sourced locally by the site.

Subjects

Subjects were healthy premenopausal female subjects aged 18–50 years, with a BMI of 18–35 kg/m2 and body weight ≥50 kg. Key exclusion criteria are described in Methods S5.

Assessments

For EE and LVG, the following PK parameters were calculated on Day 21 of each treatment period (final day of OC administration): area under the plasma concentration–time curve from time zero to the end of the dosing interval (tau) at steady state (AUCtau,ss), observed maximum plasma concentration following drug administration at steady state (C max,ss), T max, CL/F, Vz/F, and T 1/2. For icenticaftor, the following PK parameters were calculated on Day 21 of the last treatment period: AUCtau,ss, C max,ss, T max, CL/F, and Vz/F (Methods S5).

PD assessments included follicle‐stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, sex hormone–binding globulin, and follicle size determined using transvaginal ultrasound.

Safety assessments included AE and SAE monitoring as well as vital signs, laboratory values, and physical condition.

Statistical analysis

PK parameters were determined using the actual recorded sampling times and noncompartmental methods (Phoenix® WinNonlin® Version 6.2, Certara, Princeton, NJ, USA). Descriptive statistical summaries of the PK parameters of EE and LVG were presented to characterize the systemic exposure (C max,ss and AUCtau,ss). Ratios of the PK parameters of EE and LVG (with or without icenticaftor) and 90% CIs were calculated.

Icenticaftor PBPK model

The PBPK model‐building strategy was established using SimCYP (version 18; SimCYP Limited, a CERTARA company, Princeton, NJ, USA) as described in Methods S6. The model was established based on physicochemical and in vitro data as well as clinical data from a single and multiple ascending dose study (SAD and MAD, respectively).

RESULTS

Preclinical in vitro studies

Evaluation of icenticaftor as an inducer of drug‐metabolizing enzymes in human hepatocytes

Treatment of hepatocytes with up to 100 μM icenticaftor did not lead to significant induction of CYP1A2 mRNA (defined as ≥20% of the maximal positive control) but led to concentration‐dependent induction of CYP2B6 (mean maximal effect [E max] on mRNA, 10.3; concentration at half‐maximal effect [EC50], 26.6 μM) and CYP3A4 (mean E max, 113; EC50, 50.8 μM) mRNA (Tables S1 and S2). The corresponding rifampicin mRNA E max and EC50 values were 107 and 0.610 μM. No significant induction of CYP3A4 enzyme activity was noted; CYP2B6 enzyme activity was induced in one of three hepatocyte donor samples. CYP1A2 enzyme activity was decreased for two of three hepatocyte donors.

Assessment of CYP enzyme inhibition by icenticaftor in human liver microsomes

Experimental values for the unbound fraction of icenticaftor in microsomal incubations (f u,mic) decreased from 0.814 to 0.477 with increasing protein concentrations ranging from 0.0039 to 1 mg/mL and could be fitted to a quadratic function to describe the concentration dependency (f u,mic = 0.2571 × [icenticaftor]2–0.5798 × [icenticaftor] + 0.7995).

Icenticaftor showed unbound inhibitory potency for CYP1A2 (unbound inhibition constant for reversible inhibition [K i,u] = 1.50 μM), CYP2B6 (unbound concentration of inhibitor producing 50% inhibition of probe substrate metabolism [IC50,u]/2 = 35.5 μM), CYP2C9 (K i,u = 9.70 μM), CYP2C19 (K i,u = 10.5 μM), and CYP2E1 (IC50,u/2 = 24 μM; Table S3). Very little or no reversible inhibition of CYP2A6, CYP2C8, CYP2D6, or CYP3A4/5 was observed at icenticaftor concentrations of up to 100 μM. Time‐dependent/irreversible inhibition by icenticaftor was observed for CYP3A4/5‐mediated midazolam 1′‐hydroxylation (unbound inhibition constant for time‐dependent, irreversible inhibition [K I,u] = 72.2 μM; maximal rate of enzyme inactivation [k inact] = 0.034 min−1) and CYP2B6‐mediated bupropion hydroxylation (K I,u = 11.4 μM; k inact = 0.0275 min−1; Table S3).

Assessment of CYP enzyme inhibition by the icenticaftor metabolite CKW231 (M8) in human liver microsomes

With 1 and 20 μM CKW231, f u,mic values ranged between 0.884 ± 0.037 and 1.034 ± 0.221, with protein concentrations increasing from 0.01 to 1 mg/mL. CKW231 showed very little or no reversible inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 at CKW231 concentrations of up to 100 μM and did not lead to time‐dependent inhibition of any of the CYP probe substrates.

Static‐mechanistic DDI assessment of icenticaftor as a perpetrator of CYP enzymes

The results from the static‐mechanistic DDI assessment for CYP enzymes for 300 mg b.i.d. icenticaftor at steady state are shown in Table S4. For icenticaftor, weak inhibition of CYP1A2 and CYP3A4 and moderate inhibition of CYP2B6 were indicated (AUC ratio: 1.35, 1.86, and 2.11, respectively). Additionally, moderate induction of CYP3A4 was indicated (AUC ratio: 0.47). Taking the effects of time‐dependent inhibition and induction together, the net effect for CYP3A4 was AUC ratios of 0.92 (liver) and 0.79 (intestine). The combination of both organs was estimated to result in a midazolam AUC ratio of 0.73. Pregnane X receptor–mediated induction of CYP2C8, CYP2C9, and CYP2C19 could not be excluded; therefore, substrates of all five enzymes (CYP2C8, CYP2C9, CYP2C19, CYP1A2, and CYP3A4) were investigated for interactions with icenticaftor in the clinical DDI CYP substrate cocktail study.

Clinical DDI studies

CYP substrate cocktail study

Subjects

In total, 27 subjects were enrolled in the study, and 26 (96.3%) completed the study. One subject discontinued before Treatment Period 2 (physician's decision). Most subjects were male (22 [81.5%]), and the mean (standard deviation [SD]) age was 40.3 (8.85) years (Table S5).

PK results

Icenticaftor increased caffeine AUClast and AUCinf by 3.25‐ and 3.35‐fold, respectively, without increasing C max (Table 1). Icenticaftor decreased midazolam exposure (C max, AUClast, and AUCinf) by approximately 0.5‐fold. Icenticaftor decreased repaglinide C max, AUClast, and AUCinf by approximately 0.55‐, 0.65‐, and 0.66‐fold, respectively. S‐warfarin exposure (C max, AUClast, and AUCinf) was similar with or without icenticaftor. Icenticaftor increased omeprazole C max, AUClast, and AUCinf by approximately 2.55‐, 3.65‐, and 2.70‐fold, respectively. Summary statistics for the PK parameters are listed in Tables S6–S10. Concentration–time curves are displayed in Figure 3.

TABLE 1 Primary PK parameters of CYP substrates in blood and plasma (CYP substrate cocktail study).

Comparator	Parameter	Icenticaftor + 5‐probe cocktail	5‐Probe cocktail	GMR	90% CI	
Geometric LSMs	n	Geometric LSMs	n	
Caffeine	C max (ng/mL)	2560	26	2380	25	1.08	1.05–1.11	
AUClast (ng*h/mL)	61,600	26	19,000	25	3.25	2.99–3.54	
AUCinf (ng*h/mL)	66,800	24	19,900	25	3.35	3.07–3.65	
Midazolam	C max (ng/mL)	10.6	26	20.5	27	0.52	0.45–0.59	
AUClast (ng*h/mL)	25.5	26	50.6	27	0.50	0.45–0.56	
AUCinf (ng*h/mL)	27.2	26	53.4	27	0.51	0.46–0.56	
Repaglinide	C max (pg/mL)	7150	26	13,000	27	0.55	0.49–0.62	
AUClast (pg*h/mL)	13,700	26	21,000	27	0.65	0.60–0.71	
AUCinf (pg*h/mL)	13,600	24	20,400	22	0.66	0.61–0.73	
S‐warfarin	C max (ng/mL)	211	26	208	27	1.01	0.93–1.10	
AUClast (ng*h/mL)	7410	26	6750	27	1.10	1.05–1.15	
AUCinf (ng*h/mL)	7780	21	7480	20	1.04	0.97–1.12	
Omeprazole	C max (ng/mL)	463	26	182	27	2.55	1.83–3.56	
AUClast (ng*h/mL)	1490	26	408	27	3.65	2.85–4.67	
AUCinf (ng*h/mL)	1820	9	673	13	2.70	1.84–3.96	
Note: The mixed‐effects models included treatment as a fixed effect and subject as a random effect. Geometric LSMs were calculated by exponentiating the LSMs derived from ANOVA. Two subjects (icenticaftor + 5‐probe cocktail group) had predose concentrations >5% of C max for caffeine and were excluded from statistical analysis. AUCinf for caffeine was excluded from statistical analysis for two subjects (5‐probe cocktail group) because their AUC%extrap was greater than 20%. AUCinf for repaglinide could not be determined for five subjects in the icenticaftor + 5‐probe cocktail group and two subjects in the 5‐probe cocktail group because the elimination phase was not well characterized. AUCinf for S‐warfarin could not be determined for one subject in the icenticaftor + 5‐probe cocktail group because the elimination phase was not well characterized. AUCinf was also excluded from statistical analysis for seven subjects in the icenticaftor + 5‐probe cocktail group and four subjects in the 5‐probe cocktail group because their AUC%extrap was greater than 20%. AUCinf for omeprazole could not be determined for 13 subjects in the icenticaftor + 5‐probe cocktail group and 17 subjects in the 5‐probe cocktail group because the elimination phase was not well characterized. AUCinf for omeprazole was excluded from the statistical analysis for one subject in the icenticaftor + 5‐probe cocktail group because AUC%extrap was greater than 20%.

Abbreviations: ANOVA, analysis of variance; AUC%extrap, percent of AUCinf extrapolated; AUCinf, area under the concentration–time curve from time zero to infinity; AUClast, area under the concentration–time curve from time zero to the last measurable concentration sampling time; CI, confidence interval; C max, maximum (peak) observed drug concentration; CYP, cytochrome P450; GMR, geometric mean ratio; LSM, least square mean; n, number of subjects; PK, pharmacokinetics.

FIGURE 3 Arithmetic mean plasma concentration–time profiles (CYP substrate cocktail study) in semi‐log scale. (a) Caffeine, (b) midazolam, (c) repaglinide, (d) S‐warfarin, and (e) omeprazole. CYP, cytochrome P450.

Safety

No deaths, SAEs, or subject discontinuations due to AEs were reported. All AEs were mild or moderate in severity (Results S1, Table S11). Overall, 105 treatment‐emergent adverse events (TEAEs) were reported in 21 (77.8%) subjects. Hypoglycemia (serum glucose <75 mg/dL), the most common TEAE, was reported in 20 (74.1%) subjects in the study and occurred mainly with the CYP cocktail in Treatment Period 1.

OC study

Subjects

In total, 45 subjects were enrolled in the study, and 39 (86.7%) completed the study. Six subjects (13.3%) discontinued the study; five discontinued the study medication before completing the study (three at the sponsor's request and two at the subjects' request); and one withdrew consent. All subjects were female, with a mean age (SD) of 28.1 (6.19) years and mean (SD) BMI of 24.67 (3.803) kg/m2 (Table S12).

PK and PD analysis results

Multiple‐dose administration of 450 mg b.i.d. icenticaftor significantly reduced AUCtau,ss and C max,ss by 52% and 51% for EE and by 45% and 41% for LVG, respectively (Table 2). Following administration of 450 mg b.i.d. icenticaftor with EE and LVG, the mean AUC0‐12h,ss, estimated AUCtau,ss, and C max,ss for icenticaftor were 32,200 h*ng/mL, 64,400 h*ng/mL, and 4820 ng/mL, respectively. Summary statistics for the PK parameters are listed in Table S13. Concentration–time plots for EE and LVG are shown in Figure 4.

TABLE 2 Statistical analysis of treatment difference ratio for PK parameters (AUCtau,ss and C max,ss) of EE and LVG (OC study).

Comparator	Parameter	Icenticaftor + OC	OC	GMR	90% CI	
Geometric LSMs	n	Geometric LSMs	n	
EE	AUCtau,ss (h*pg/mL)	353.819	39	735.505	39	0.481	0.446–0.519	
C max,ss (pg/mL)	43.616	39	89.761	39	0.486	0.446–0.529	
LVG	AUCtau,ss (h*pg/mL)	44,615.792	39	81,558.915	39	0.547	0.515–0.581	
C max,ss (pg/mL)	4148.129	39	7064.640	39	0.587	0.548–0.629	
Abbreviations: AUCtau,ss, area under the plasma concentration–time curve from time zero to the end of the dosing interval tau at steady state; CI, confidence interval; C max,ss, observed maximum plasma concentration following drug administration at steady state; EE, ethinyl estradiol; GMR, geometric mean ratio; LSM, least‐squares mean; LVG, levonorgestrel; n, number of subjects; OC, oral contraceptive; PK, pharmacokinetics.

FIGURE 4 Arithmetic mean (SD) concentration–time plot of (a) EE and (b) LVG in the OC study. EE, ethinyl estradiol; LVG, levonorgestrel; OC, oral contraceptive; SD, standard deviation.

FSH, LH, estradiol, and Hoogland scores were higher with icenticaftor–OC co‐administration than with OC alone, which is consistent with reduced exposure to OC during icenticaftor–OC co‐administration compared with OC alone (Table S14).

Safety

No severe AEs were reported in this study. Most AEs were mild, and six were moderate in severity. No deaths were reported in the study. None of the subjects discontinued due to AEs. One SAE was reported in one subject (injury), which was not suspected to be related to the study medication. Overall, 35 (77.8%) subjects reported at least one AE throughout the study, and the most common AE was nausea (Results S2, Table S15).

Icenticaftor PBPK model

The icenticaftor PBPK model was successfully established (Data S1). The nonlinear icenticaftor PK with increasing doses was well predicted for the SAD/MAD PK data (Figure S1), as well as the PK profile at a dose of 300 mg b.i.d. at Day 6 (Figure S2). The icenticaftor PBPK model based on the in vitro CYP inhibition data underpredicted the DDI effect for CYP1A2 and CYP2C19. To improve the prediction of the caffeine DDI effect, the CYP1A2 K i,u value in the icenticaftor PBPK model had to be lower by 75‐fold, from 1.5 to 0.02 μM. Similarly, to reproduce the icenticaftor DDI effect on omeprazole, the CYP2C19 K i,u value had to be lower by 350‐fold, from 10.5 to 0.03 μM. Using the in vitro induction parameters of hepatocyte Donor 2 and leaving out the CYP3A4/5 time‐dependent inhibition parameter, as no time‐dependent inhibition was observed with hepatocytes (data on file), the DDI effect on midazolam was well predicted (Table S16). The induction effect of icenticaftor on repaglinide was underpredicted by the PBPK model when considering only the induction of CYP3A4 and CYP2C8, even by increasing the induction effect on CYP2C8 substantially (data on file). The input parameters for the PBPK model are shown in Table S17, and the predicted DDI data for icenticaftor as a victim and mefenamic acid as an inhibitor are shown in Table S18.

A uridine diphosphate glucuronosyltransferase (UGT) enzyme, UGT1A9, was identified as the major clearance pathway of icenticaftor (fraction metabolized: 68%–78%). 3 Therefore, it was important to understand the DDI potential of icenticaftor as a substrate of this pathway. When using the established icenticaftor PBPK model (300 mg b.i.d.) with the UGT1A9 inhibitor mefenamic acid (500 mg 4× daily), icenticaftor C max and AUC were predicted to increase by 1.13‐ and 1.22‐fold, respectively, indicating no sensitivity toward mefenamic acid–mediated UGT1A9 inhibition.

DISCUSSION

Determining the DDIs of new compounds is an important aspect of drug development, and both the FDA and EMA have provided guidelines for evaluating DDIs. 4 , 5 Data from in vitro studies indicated that icenticaftor may induce the metabolic clearance of co‐medications metabolized by CYP3A4 and potentially CYP2C enzymes and may inhibit the metabolic clearance of co‐medications metabolized by CYP1A2, CYP2B6, and CYP3A4/5, based on a static‐mechanistic DDI risk assessment with unbound icenticaftor portal vein concentrations at steady state for the 300 mg b.i.d. dose. Due to the time‐dependent inhibition of CYP3A4/5 and CYP2B6, the decrease in enzyme activity of these CYP enzymes may be amplified by administering multiple doses. Icenticaftor is neither expected to inhibit human CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 nor to induce CYP1A2 or CYP2B6.

Based on these in vitro findings, further clinical DDI studies were required to investigate other potential DDIs of icenticaftor. The induction of CYP2C8, CYP2C9, and CYP2C19 is regulated by the same promoter as that for CYP3A4, the pregnane X receptor 6 ; therefore, substrates of these enzymes were included in the CYP substrate cocktail DDI study. Icenticaftor increased caffeine AUClast and AUCinf by more than 3‐fold without increasing C max, which suggests that icenticaftor moderately inhibits CYP1A2. Icenticaftor decreased midazolam exposure by 0.5‐fold and repaglinide exposure (C max, AUClast, and AUCinf) by 0.55‐, 0.65‐, and 0.66‐fold, suggesting weak induction of CYP3A and CYP2C8. The effect on repaglinide may have been a result of the combined contribution of both CYP2C8 and CYP3A4 induction because repaglinide is a substrate of both enzymes. 7 S‐warfarin exposure was not affected by icenticaftor, suggesting that icenticaftor does not have a relevant effect on CYP2C9. Icenticaftor increased omeprazole C max, AUClast, and AUCinf by 2.55‐, 3.65‐, and 2.70‐fold, suggesting that icenticaftor moderately inhibits CYP2C19. The observation that icenticaftor 300 mg b.i.d. moderately inhibited CYP1A2 and CYP2C19 was unexpected based on the static‐mechanistic DDI assessment, which predicted weak inhibition for CYP1A2 and no inhibition (<1.25) for CYP2C19. As expected from the results with CYP3A4 from the in vitro studies, weak induction was observed for CYP2C8 and CYP3A4.

In the OC DDI study, co‐administration of icenticaftor 450 mg b.i.d. significantly reduced the plasma exposure (AUC and C max) of both components of the OC (EE and LVG) by approximately 50% and 40%, respectively, likely due to the induction of CYP3A4 enzymes that play a key role in metabolizing EE and LVG. 8 , 9 The increased levels of PD parameters (FSH, LH, estradiol, and Hoogland scores) are consistent with the reduced exposure of OC. These results demonstrate that OC cannot be used effectively when co‐administered with icenticaftor; therefore, alternative contraceptive methods need to be used.

No safety concerns were identified in either the DDI or the OC study, and co‐administration of icenticaftor with caffeine, midazolam, repaglinide, S‐warfarin, and omeprazole was generally well tolerated.

The PBPK model described the icenticaftor PK across the dose range of 10–1000 mg well, although the PK increased in a nonlinear manner. Saturation of UGT1A9 is believed to be the driver of PK nonlinearity based on its low K m,u value of 0.17 μM (Table S17). PBPK modeling demonstrated that in vitro K i,u values for reversible inhibition of CYP1A2 and CYP2C19 had to be decreased by 75‐ and 350‐fold to match the clinical DDI effects. Reversible inhibition of CYP enzymes can generally be determined with good precision; therefore, it is unlikely that these two parameters were merely poorly determined. CYP inhibition by metabolites or downregulation of the respective CYP enzymes could also explain the pronounced CYP1A2 and CYP2C19 inhibition observed in the clinical DDI study. In vitro induction data of CYP1A2 (based on enzyme activity) showed decreased activity for two of three hepatocyte donors; the mRNA levels remained unchanged. The major metabolite, CKW231, a direct glucuronide, was investigated for CYP inhibition, and the results did not reveal any inhibition potential. Two more glucuronide metabolites were identified as major metabolites (M5 and M9) with >10% of total drug‐related AUC, which could be responsible for the inhibition effect. 3 However, this is considered unlikely, as CYP inhibition has not been observed for the structurally similar major metabolite CKW231. Finally, it is difficult to decide whether the CYP1A2 and CYP2C19 inhibition effects observed are related to enzyme downregulation based on the available data. Apart from this limitation, the icenticaftor PBPK model could not replicate the observed CYP2C8 induction effect on repaglinide well because of a lack of in vitro CYP2C8 and organic anion transporting polypeptide (OATP)1B induction parameters and the fact that OATP1B is poorly inducible by pregnane X receptor inducers. 10

PBPK simulation predicted almost no exposure change when co‐administering icenticaftor with the UGT1A9 inhibitor mefenamic acid, which is explained by the saturation of intestinal UGT1A9 with icenticaftor 300 mg b.i.d. and the low systemic mefenamic acid concentration (C max,ss,u < 2.86 μM, based on PBPK model optimization [data on file]) relative to its UGT1A9 K i,u value of 4.05 μM (based on PBPK model optimization [data on file]) as well as a rapid decline in plasma concentrations due to a T 1/2 of 2–4 h. Icenticaftor is one of the few drugs for which the major clearance pathway is through UGT, with a Michaelis–Menten constant (K m) value of <1 μM.

In conclusion, results from the CYP substrate cocktail DDI study indicate weak induction of CYP3A4 and CYP2C8 and moderate inhibition of CYP1A2 and CYP2C19. Static mechanistic DDI assessment indicated potential moderate induction of CYP3A4, weak inhibition of CYP1A2 and CYP3A4, and weak to moderate inhibition of CYP2B6. Icenticaftor reduced the plasma exposure of both components of the OC (EE and LVG) by 50%. These results provide guidance on the safe use of icenticaftor in patients who take concomitant medications that are substrates of certain CYP enzymes (CYP1A2, CYP3A, CYP2C8, and CYP2C19) or inhibitors of UGT1A9 as well as in patients who use OCs. The results can therefore provide information for label development and aid in the selection of potential exclusion criteria for upcoming icenticaftor clinical trials.

AUTHOR CONTRIBUTIONS

F.H., U.G., A.D., W.W., J.Z., and L.B. wrote manuscript. F.H., A.D., and W.W. designed research. A.D., and W.W. performed research. F.H., U.G., A.D., W.W., J.Z., and L.B. analyzed data.

FUNDING INFORMATION

The study was funded by Novartis Pharma AG, Basel, Switzerland.

CONFLICT OF INTEREST STATEMENT

All authors are employees of Novartis. All authors except LB hold Novartis shares. The authors declared no other competing interests for this work.

Supporting information

Data S1.

ACKNOWLEDGMENTS

Financial support for medical editorial assistance was provided by Novartis Pharma AG, Basel, Switzerland. We thank Sorcha Mc Ginty, PhD (Novartis Global Business Solutions, Dublin, Ireland), Cathy Mc Donnell, PhD (Novartis Global Business Solutions, Dublin, Ireland), and Rina Vekaria Passmore, PhD (Novartis Global Business Solutions, London, UK) for medical editorial assistance with this manuscript.
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