Severe Impact of Omeprazole Timing on pH‐Sensitive Dasatinib Absorption: Unveiling Substantial Drug–Drug Interaction

Abstract

The absorption and bioavailability of most tyrosine kinase inhibitors are affected by gastrointestinal pH as they are weak basic lipophilic drugs. Hence, concomitant use of acid reducing agents (ARAs) is frequently restricted. Particularly comedication of crystalline dasatinib (Sprycel) and proton‐pump inhibitors (PPIs) should be avoided. Drug–drug interaction (DDI) studies with PPIs report approximately 40%‐80% bioavailability reduction of dasatinib. Limitations in the design of these studies do not allow for assessing the near maximum DDI as timing of PPI dosing was either not reported or 22 h prior to dasatinib intake. We conducted a DDI study of crystalline dasatinib and omeprazole in healthy, fasted participants, investigating the impact of PPI comedication on dasatinib plasma exposure at a time point when the near maximum DDI effect is expected. Participants were administered omeprazole (day 2‐5) to reach steady state. On day 6, a single dose of crystalline dasatinib was given. Crystalline dasatinib dosing alone on day 1 served as control (single dose). The dosing interval between omeprazole administration and crystalline dasatinib was 10 h (median [range: 9‐10 h]). Dasatinib C_max and AUC_0‐24 were reduced by 96% and 89% by omeprazole comedication. C_max was 224.6 ± 104.7 ng/mL (mean ± SD) and 8.0 ± 4.5 ng/mL (P < .0001) and AUC_0‐24 was 797.6 ± 274.5 and 90.6 ± 38.1 h·ng/mL (P < .0001) without and with omeprazole. T_1/2 was 5.7 ± 1.5 h (mean ± SD) with crystalline dasatinib dosing alone and could not be reliably calculated with comedication. To ensure optimal patient outcome, it is vital to investigate bioavailability of pH‐sensitive drugs at the maximal DDI effect of ARAs to understand the worst‐case influence for efficient clinical management.

Introduction

Drug–drug interactions (DDIs) are common in cancer pharmacotherapy due to the need for medication of patients’ multimorbidity and the toxicity of cancer drugs. ¹ , ² Protein kinase inhibitors (PKIs), including the subcategory of tyrosine kinase inhibitors (TKIs), are primarily oral administered cancer drug products that are commonly affected by DDIs via the complex gastrointestinal (GI) absorption process and first pass effect in the gut and/or liver. ³ , ⁴ The majority of DDIs for PKIs/TKIs are related to reduced GI absorption, induced/inhibited drug membrane transport, and/or metabolism. ⁵ , ⁶ , ⁷ Drug membrane transport and metabolic mediated DDIs might be managed with dose adjustments, however, severely reduced GI absorption is challenging to manage as the majority of the drug dose is not absorbed. Concomitant use of gastric acid reducing agents (ARAs), such as proton‐pump inhibitors (PPIs) decreases the GI absorption of many PKIs due to their low and strong pH‐dependent solubility and absorption, this can significantly decrease plasma exposure and potentially diminish the anti‐cancer effect in patients. ⁸ , ⁹ Hence, DDIs caused by ARAs are of major clinical concern during oral PKI therapy and the concomitant use of ARAs with many PKIs is restricted to delayed dosing or prohibited. ⁹ , ¹⁰

In particular crystalline formulated dasatinib (Sprycel), a TKI used for the treatment of chronic myelogenous leukemia (CML) and acute lymphatic leukemia (ALL), is strongly affected by the DDI with ARAs. Consequently, concomitant antacids should be dosed within a specific time interval prior to crystalline dasatinib, whereas PPIs and H₂‐receptor antagonists (H₂‐RAs) should not be co‐administered during the therapy with crystalline dasatinib. ¹¹

PPIs are among the most commonly prescribed medications in clinical practice and are weak acid labile drugs that reduce gastric acid secretion by inhibition of the H⁺–K⁺ ATPase in the parietal cells in the stomach. ¹² , ¹³ , ¹⁴ PPIs suppress gastric acid secretion and constitute the first‐line treatment for gastric acid‐related disorders such as gastroesophageal reflux disease (GERD), dyspepsia, gastritis, and peptic ulcer disease. ¹⁵ , ¹⁶ Luminal stomach pH must be maintained at ≥4.0 to successfully treat acid‐related diseases. ¹⁷ However, PPIs have a slow onset of action, which is a drawback to on‐demand therapy, and nocturnal acid breakthrough, resulting in interrupted gastric pH suppression and symptom breakthrough. ¹⁸

The duration of, and the decline in the effect on H⁺–K⁺ ATPase mediated acid secretion by PPIs within a dosing interval have clinical implications impacting DDIs. It is therefore critical to consider the timing of PPI and TKI dosing to assess the maximal DDI effect and its clinical implication. ¹⁸ DDI‐magnitude of the various TKIs and ARAs as well as its influence on therapeutic response differ depending on the properties of the TKI. ¹ , ⁹ , ¹⁰ , ¹⁹ , ²⁰

In the case of crystalline dasatinib in oral drug products, the reduced plasma exposure caused by concomitant use of ARAs may significantly reduce the therapeutic response and lead to disease progression in patients. ¹¹ , ²¹ , ²² The plasma exposure of dasatinib is reduced by approximately 60% after single dose of crystalline dasatinib (50 mg) when administered 10 h after a famotidine (H₂RA) 40 mg evening dose. ¹⁰ In addition, dasatinib plasma exposure was reduced by ∼55% to 58% when co‐administered with aluminum hydroxide/magnesium hydroxide suspension‐based antacids but unaffected when administered 2 h prior to crystalline dasatinib. ¹⁰ For PPIs, the reported reduction in absorption and bioavailability of dasatinib reaches approximately 40% and as much as 80% when the experimental setting is controlled for gastric pH above 4. ²³ , ²⁴ , ²⁵ , ²⁶ The design of most DDI studies with PPIs does however not allow to investigate the near maximum effect on dasatinib bioavailability, as the dosing of the selected PPI was not reported or 22 h prior to dasatinib dosing. ²³ , ²⁴ , ²⁵ , ²⁶ The maximum DDI of a PPI unfold when the interval between PPI and dasatinib dosing is approximately between a minimum of 4 h and a maximum of 16 h, and is expected to result in a substantially lower bioavailability of dasatinib. ¹⁸ , ²⁷ , ²⁸ Based on this background we conducted a DDI study of omeprazole and crystalline dasatinib with the main objective to investigate the impact on the GI absorption and bioavailability of dasatinib with PPI comedication at a time point when the near maximum DDI effect on bioavailability is expected.

Material and Methods

Overall Study Design and Study Drugs

This was an open‐label, non‐randomized, two‐treatment, single‐period, single‐dose, DDI study in healthy participants to evaluate the near maximum DDI effect between 100 mg crystalline dasatinib immediate release (IR) (Sprycel 100 mg Film‐Coated Tablets; Bristol‐Myers Squibb Company Princeton) and 40 mg omeprazole delayed release (omeprazole, 40 mg, delayed release Dr. Reddy's Laboratories, Bachupally, India) when omeprazole was dosed in the evening and 10 h preceding crystalline dasatinib dosing in the fasted state (Figure 1). The main inclusion criteria included healthy adults between 18 and 45 years of age (both inclusive) weighing at least 50 kg; having body mass index (BMI) between 18.5 and 29.9 kg/m² (both inclusive) (for detailed information, see Supplemental Information). A sample size of 18 participants was selected based on the reported reduction of 43% on dasatinib plasma exposure when omeprazole and crystalline dasatinib was co‐administered at an interval of 22 h. ²⁶ In our setting with a dosing interval of 10 h, a significantly higher DDI effect on dasatinib absorption and bioavailability was expected. Based on previous experience and intraindividual variability in pharmacokinetics a sample size of 18 participants was deemed appropriate to describe the DDI effect. ²⁶

Figure 1.

Study design of the open‐label, non‐randomized, two‐treatment, single‐period, single‐dose, drug–drug interaction study

Crystalline dasatinib (100 mg, IR tablet) was administered by mouth alone (control) on day 1 and on day 6 (test) in the morning (8:00‐8:30 a.m.) with a glass of water (approximately 240 mL at room temperature). Participants had been fasting for at least 10 h before and 4 h after intake of crystalline dasatinib and this served as its own control on days 1 and 6 (Figure 1).

On days 2 to 5, single oral doses of omeprazole 40 mg (delayed release) enteric‐coated capsule were administered once daily (QD) between 10:30 and 11:00 p.m. with about 150 mL of drinking water. Once daily dosing over 4 days was selected to ensure steady state was reached prior to second dosing of dasatinib (Figure 1). On day 5, omeprazole was administered between 10:30 and 11:00 p.m. followed by crystalline dasatinib dosing in fasted state on day 6 between 8:00 and 8:30 a.m. The timing for omeprazole dosing prior to dasatinib dosing on day 6 (9.0‐10.0 h) prior to dasatinib dosing was selected to investigate a scenario when the near maximum therapeutic effect of omeprazole (gastric pH >4) is expected. ¹⁸ , ²⁷ , ²⁸

On all study days, each participant was dosed in sitting posture in the presence of the principal investigator. Further the participants were instructed not to chew or crush the tablets/capsules and to swallow these intact. Oral cavity check was carried out immediately after administration. Any participant who did not follow the dosing instruction was withdrawn from the study. Participants were observed for adverse events, 12‐lead ECG, vital signs, body temperature, and well‐being during the study. All participants underwent 12‐lead ECG, vital signs, body temperature, and well‐being check prior to leaving the study site and hematology, clinical chemistry, were done after the study for monitoring purposes.

Selection of Doses in the Study

The dose of 100 mg crystalline dasatinib was selected to be a safe dose based on regulatory recommendations, the sponsor's earlier experience and published clinical literature. Further, the 100 mg crystalline dasatinib was expected to achieve sufficient plasma concentration–time profiles for pharmacokinetic (PK) assessment in healthy participants even after repeated oral dosing of omeprazole. The dose of 40 mg omeprazole was selected as this is the indicted oral dose for patients with gastric ulcers and was considered safe based on regulatory recommendations. ²⁹

Dosing in Fasted State and in Relation to Food Intake

Each participant who passed the screening procedure was admitted to the study center at least 11 h prior to drug administration and was checked out on day 7 after the last drawn PK sample (Figure 1). A pre‐study dinner was served to all participants (day 0). All the participants were fasted for at least 10 h prior to drug administration on study days 1 and 6, respectively. Fasting condition continued as no food was allowed for at least 4 h post dose of crystalline dasatinib.

On day 1, a standardized lunch, snacks and dinner were served to all the participants at about 4, 8, and 12 h post dose of crystalline dasatinib, respectively. On day 2 through day 5, standardized breakfast, lunch, snacks, and dinner were served to each participant at about 8, 13, 17, and 20 h post dose of omeprazole. No food was allowed within 2 h before and 1 h after administration of omeprazole except on day 5. On day 5 food was not allowed after 8.30 p.m. and each participant stayed overnight at the clinic. On day 6, each participant was fasted prior to crystalline dasatinib dosing and standardized lunch, snacks, dinner, and breakfast were served to each participant at about 4, 8, 12, and 24 h post dose of crystalline dasatinib, respectively. The calories of all the meal contents were similar for all the participants throughout the study. No caffeine/xanthine, alcohol, or grapefruit containing products was provided by the clinic staff during confinement.

Plasma Samples

Blood samples (3 mL) were collected by direct venipuncture in Vacutainer containing K₂EDTA at pre‐dose (0.0 h), within 60 min prior to crystalline dasatinib administration on day 1 and day 6, at 0.25, 0.33, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 16.0, 20.0, and 24.0 h post dose (±2 min). The blood samples were kept at room temperature (max 90 min) until centrifuged (3000 revolutions per minute at 4°C for 10 min) to separate the plasma. Plasma samples were stored at −70 ± 15°C. The plasma samples were stored for a maximum period of 6 months from the study analysis completion date.

Dasatinib plasma concentration where quantified using a LC‐MS/MS method which was developed and validated for selectivity, linearity, reproducibility, recovery, precision, and accuracy at QPS Bioserve India Pvt. Ltd., India. The linear dynamic range of the method in human plasma containing K₂EDTA was from 0.75 to 600.8 ng/mL, with lower limit of quantification (LLOQ) of 0.75 ng/mL. The assay utilized a liquid–liquid extraction procedure using ethyl acetate as extraction solvent, requiring 100 µL of plasma spiked with stable label internal standard (dasatinib‐d8). Samples were chromatographically separated on an Agilent Extend C18, 5 µm, 4.6 × 150 mm column by an isocratic method using 100% methanol and 0.1% formic acid in water at 70:30 ratio. Total run time for a 10 µL injection was 2.8 min per sample. The quantitative LC‐MS/MS method used multiple reaction monitoring (MRM) with m/z monitored for dasatinib 488.3/401.1 and dasatinib‐d8 496.3/406.1 using positive ion electrospray ionization (ESI) with an ion spray voltage of 5500 V. Within day accuracy 98.0% to 108.7% and precision 0.7 to 5.3 %CV. Between day accuracy 100.9% to 104.9% and precision 3.1 to 6.3 %CV.

Data Analysis

Dasatinib Pharmacokinetic Data Analysis

The PK analyses were based on assessment of plasma concentration–time profiles of dasatinib and were calculated on day 1 (only crystalline dasatinib treatment) and day 6 (crystalline dasatinib and omeprazole delayed release treatment) for each participant by using non‐compartmental PK methods (Phoenix WinNonlin 8.3 software was used from Certara USA Inc., Princeton, NJ). They included C_max (maximum plasma concentration), AUC_0‐24 (area under plasma concentration–time curve during the first 24 h), AUC_0‐inf (area under plasma concentration–time curve from time zero to infinity), T_max (time of the maximum plasma concentration), Kel (apparent first‐order terminal elimination rate), and terminal half‐life (t_1/2). AUC_0‐inf was calculated using extrapolation from time of last measurable concentration to infinity. Key assumptions were that the plasma concentration–time profile decreases in a mono‐exponential manner and that the terminal rate constant is not affected by absorption. The PK variable values were summarized by treatment day using descriptive statistics. For dasatinib C_max, AUC_0‐24, and AUC_0‐inf the ratio of the population geometric means (day 6/day 1) with 90% confidence intervals was calculated. Demographics and baseline data were summarized by descriptive statistics.

Statistics

The PK and statistical analysis were performed on participants who completed the DDI study and all samples were analyzed in the bioanalytical laboratory for dasatinib. Descriptive statistics (such as mean, median, minimum, maximum, standard deviation, geometric mean, and coefficient of variation [CV%]) for relevant PK parameters (C_max, AUC_0‐24, AUC_0‐inf, AUC_{extrapolation}, T_max, t_1/2, and Kel) were estimated for crystalline dasatinib alone and crystalline dasatinib together with PPI comedication. Based on pairwise comparisons of the ln‐transformed C_max, AUC_0‐24, AUC_0‐inf data, the ratios of the least‐squares mean values were calculated, as well as the 90% confidence intervals for ln‐transformed C_max and AUC_0‐inf were determined. Log‐transformed PK parameters (C_max, AUC_0‐24 and AUC_0‐inf) were analyzed using an analysis of variance (ANOVA) model at alpha 0.05 using the SAS Studio 3.6 (Basic Edition) (SAS Institute Inc., USA). The ANOVA model included treatment as fixed effects. The 90% confidence intervals for the difference between treatments least‐square means (crystalline dasatinib only and crystalline dasatinib with PPI comedication) were calculated for ln‐transformed C_max, AUC_0‐24 and AUC_0‐inf.

Ethical Considerations

The clinical trial complied with the ethical principles set forth in the New Drugs and Clinical Trials Rules of India, the Declaration of Helsinki, and the International Conference on Harmonization (ICH‐E6, R2) Good Clinical Practice Guidelines (GCP). The protocol was reviewed and approved on August 21, 2023 by national regulatory authorities (Drugs Controller General India) and the institutional review board (QPS Bioserve Ethics Committee, Hyderabad, India) before implementation. The study is registered with ClinicalTrials.gov (Identifier: NCT06145217). All participants provided written informed consent prior to dosing of test and reference items in the study. In accordance with the ICH‐GCP guidelines, all participants had the right to withdraw from the study at any time, regardless of their reasons. Over the course of the study, the investigator(s) had the right to withdraw any participant from the study as provided in the Supplemental Information.

This comparative bioavailability study was conducted according to Good Laboratory Practice (GLP) at a research facility (QPS Bioserve India Pvt. Limited, Hyderabad, India).

Results

Demographics of Participants

A total of 18 healthy male participants were included. Participants were between 24 and 42 years of age (median 34). The median height was 167 cm (range 152‐175), median body weight was 69.1 kg (range 52.5‐82.6), and median BMI was 24.2 kg/m² (range 19.0‐28.8). All were non‐smoker and non‐alcoholic, and each participant was healthy according to medical history, clinical examination, and laboratory screening tests (see Table S1 in the Supplemental Information for demographics).

Dosing Interval Between Omeprazole and Crystalline Dasatinib, and Schedule for Plasma Sampling for Dasatinib Quantification and PK Analysis

All participants were dosed with 100 mg crystalline dasatinib on day 1 and 40 mg omeprazole on days 2‐5 as per protocol. All participants were dosed with omeprazole between 10:30 and 11:00 p.m. on day 5 (the day prior to dosing of crystalline dasatinib) and with crystalline dasatinib between 08:00 and 08:16 a.m. on day 6. The median time between omeprazole dosing (day 5) and crystalline dasatinib dosing (day 6) was 10 h (range: 9‐10 h). All participants remained in the fasted state for at least 2 h prior to omeprazole dosing on day 5 (evening) and at least 10 h prior to crystalline dasatinib dosing on day 6. All plasma samples were drawn within the specified scheme of ±2 min of the scheduled time after dosing with crystalline dasatinib on days 1 and 6.

Gastrointestinal (GI) Absorption and Bioavailability of Crystalline Dasatinib without and with Concomitant Omeprazole Delayed‐Release Treatment

The mean (±SD) plasma concentration–time profiles of dasatinib when given as 100 mg crystalline dasatinib alone and after concomitant dosing with omeprazole 40 mg delayed release are shown in Figure 2. The individual dasatinib plasma concentration–time profiles (N = 18) are displayed in Figure 3. The mean (±SD) PK parameters for dasatinib are shown in Tables 1 and 2. Individual AUC_0‐24 and C_max after crystalline dasatinib dosing and after comedication of crystalline dasatinib with omeprazole are shown in Figure 4 (N = 18). AUC_0‐inf and t_1/2 of dasatinib at comedication with omeprazole was not possible to calculate accurately as the plasma concentration–time curve for dasatinib was low and had not declined due to on‐going intestinal absorption from the large unabsorbed dose of dasatinib (flip‐flop pharmacokinetics) and is therefore not described herein. Time (T_max) and range to maximum plasma concentration of dasatinib was 1.2 h (0.5‐3.0) and 1.9 h (1.0‐16.0) without and with omeprazole treatment, respectively. The mean (±SD) dasatinib C_max was 224.6 ± 104.7 and 8.0 ± 4.5 ng/mL (P < .0001) when administering crystalline dasatinib formulation without and with omeprazole, respectively, resulting in a mean reduction of 96% with crystalline dasatinib and omeprazole comedication. The corresponding data for AUC_0‐24 was 797.6 ± 274.5 and 90.6 ± 38.1 ng·h/mL (P < .0001), respectively, and an 89% reduction with crystalline dasatinib and omeprazole comedication. T_1/2 was 5.7 ± 1.5 h (mean ± SD) with crystalline dasatinib dosing alone.

Figure 2.

Arithmetic mean (±SD) plasma concentration–time of dasatinib following a single‐dose oral administration of crystalline dasatinib (100 mg) (black, circle) and comedication of crystalline dasatinib (100 mg) and omeprazole (40 mg at steady state) (red, square) in fasted state in healthy subjects (N = 18).

Figure 3.

Individual plasma concentration–time profiles in healthy subjects (N = 18) during dosing with crystalline dasatinib (100 mg, single dose) (black, circles), and comedication of or crystalline dasatinib (100 mg, single dose) and omeprazole (40 mg, steady state) (red, squares). Plasma concentration axis is set to a maximum of 500, 250, or 100 ng/mL, respectively.

Table 1.

Arithmetic mean (± SD) Pharmacokinetic (PK) parameters of dasatinib following oral single dose of crystalline dasatinib (100 mg) alone and with Concomitant oral dosing of omeprazole extended release at steady state (40 mg QD for 4 days consecutively)

	Crystalline Dasatinib (Control)	Crystalline Dasatinib and Omeprazole (Test)
PK Parameter	Mean ± SD	Mean ± SD
Cmax (ng/mL)	224.6 ± 104.7 (CV% 47)	8.0 ± 4.5 (CV% 56)
AUC0‐24 (h·ng/mL)	797.6 ± 274.5 (CV% 34)	90.6 ± 38.1 (CV% 42)
T1/2 (h)	5.7 ± 1.5	NE

AUC_0‐24, area under the plasma concentration–time curve from time 0 to 24h; C_max, maximum plasma concentration; NE, not evaluable; t_1/2, terminal half‐life.

Data are presented as arithmetic means ± standard deviation [number of observations]. Coefficient of variation (CV%) (where CV% = standard deviation [SD]/mean × 100).

Table 2.

Pharmacokinetic parameters of dasatinib following oral dosing of crystalline dasatinib (100 mg) alone and with concomitant oral dosing of omeprazole extended release at steady state (40 mg QD for 4 days consecutively)

	Geometric Mean
Parameter (Unit)	Crystalline Dasatinib (Control)	Crystalline Dasatinib and Omeprazole (Test)	Ratio Test/Control (%)	90% Confidence Interval	P (ANOVA)
Cmax (ng/mL)	195.02	7.17	3.7	2.73‐4.96	<.0001
AUC0‐24 (h·ng/mL)	734.63	84.79	11.5	9.13‐14.59	<.0001
T1/2 (h)	5.5	NE

ANOVA, analysis of variance; AUC_0‐24, area under the plasma concentration–time curve from time zero to 24h; C_max, maximal plasma concentration; NE: not evaluable; t_1/2, terminal half‐life.

Figure 4.

AUC_0‐24 and C_max of dasatinib in plasma after dosing with crystalline dasatinib (100 mg, single dose) and comedication of crystalline dasatinib (100 mg, single dose) and omeprazole (40 mg at steady state) in healthy subjects (N = 18).

The mean (±SD) extrapolated area in the plasma concentration–time profile was 2.7% ± 1.3% when crystalline dasatinib formulation was administered alone. The extrapolated area could not be calculated for dasatinib with omeprazole comedication, as the plasma curve was very low and did not decline due to on‐going extended intestinal absorption from the large unabsorbed dose of dasatinib.

Safety and Tolerability

In this study, 18 adverse events (AEs) were reported by 11 (61.11%) participants (see Table S2 in the supplemental material). The treatment‐emergent (TE) AEs experienced during the study were deemed mild (77.77%) and moderate (22.22%) in intensity. None of the participants experienced a severe TEAE during the study. No SAEs or deaths were reported in any of the participants dosed in this study. None of the participants were withdrawn by the investigator due to a TEAE.

Discussion

The impact of PPIs on reduction of gastrointestinal (GI) absorption and bioavailability of the product investigated in this study, crystalline dasatinib, has been investigated in earlier DDI studies. ²³ , ²⁴ , ²⁶ In one of the previous studies, crystalline dasatinib was taken approximately 22 h (fasted state) after the final omeprazole dosing, ²⁶ a time point when the absorption of dasatinib is only moderately affected. ¹⁸ , ²⁸ Bioavailability was reported to be reduced by 43% and consequently, the combined use of crystalline dasatinib and PPIs is not recommended as the reduced bioavailability and plasma exposure may negatively influence the expected therapeutic effect and lead to disease progression. ¹⁹ , ²¹ , ²⁶

In contrast, in our DDI study (omeprazole at steady state and dosed in the evening 10 h prior to crystalline dasatinib), the GI absorption and bioavailability of crystalline dasatinib were reduced by about 90% and were evident in all participants. The reduction in absorption and bioavailability of dasatinib caused by omeprazole is more extensive than previously reported, leading to significantly reduced systemic exposure of dasatinib with a higher than previously known clinical relevance. ¹⁰ , ²⁴ , ³⁰

The magnitude of the reduction of crystalline dasatinib bioavailability when used together with PPIs is determined by the PPI‐effect duration, timing between dasatinib and PPI‐dosing and PPI‐effect duration (defined as the time period when the gastric pH is above 4). ³¹ The PPI‐effect duration is often relatively long lasting, even if the effect starts to wear‐off (i.e., gastric pH below 4) 16 h after dosing and is dependent on the pharmacological properties of the PPI, PPI dosage, PPI‐dosage form, and PPI‐dose interval. ¹⁸ , ²⁷ , ²⁸ Additionally, the current available PPIs do not allow for a near maximum pH effect over the full dosing interval of 24 h even at steady state. ²⁷ , ²⁸ In some cases, the duration of effect of PPIs can be reduced, mainly due to nocturnal acid breakthrough in patients with GERD, ³² , ³³ which is due to class‐specific factors such as short terminal half‐lives and irreversible binding to H+/K+ ATPase in the parietal cell, resulting in reduced exposure to proton pumps (H+/K+ ATPase) synthesized at night. ¹⁸ , ³⁴ , ³⁵ Further, gastric acid secretion has a diurnal rhythm, reaching its maximum between 10 p.m. and 2 a.m., possibly being the major mechanism for the nocturnal pH breakthrough. ³⁶ Hence, the interaction between GI physiology, circadian rhythm, PPI‐effect duration, pharmacodynamics, and pharmacokinetics of PPIs has a strong impact on the magnitude of DDI. Consequently, the therapeutic response to crystalline dasatinib may be affected as the plasma/blood exposure correlates with the effect of dasatinib based on large PK/PD studies. ²⁰ , ²¹ Albeit smaller retrospective clinical studies, not fully controlling for the timing of comedication and plasma exposure, failed to confirm this association, ¹⁹ , ³⁷ , ³⁸ the pharmacodynamic properties of dasatinib indicates a DDI causing substantial reduced exposure, leading to a negative impact on therapeutic response. ²¹

Based on this background, we investigated the impact of timing of dosing between PPI and crystalline dasatinib, as considered decisive to establish the maximal risk for any DDI. Our study, revealing an approximate 90% reduction of dasatinib absorption and bioavailability, together with other reports demonstrates that the time interval between intake of omeprazole and crystalline dasatinib plays a significant role on the extent of reduction of the pH‐dependent GI absorption of crystalline dasatinib. ¹⁰ , ²⁴ , ³⁰ , ³⁹ In general, the design of previous DDI studies with dasatinib and ARAs are suboptimal, not allowing to investigate the near maximum scenario as the detection of the highest DDI effect requires studying the elevation of gastric pH above 4. ¹⁸ , ²⁷ , ²⁸ In our study, the timing of dosing between omeprazole and crystalline dasatinib was set to assess the near maximum DDI effect with a high probability of gastric pH above 4. The effect in previous DDI studies was substantially lower, approximately 43% reduction, and relates to the 22 h dosing interval between PPI and crystalline dasatinib, allowing the pH to decrease as the PPI effect weans off at the end of the dosing interval of the PPI ²⁶ , ²⁷ , ²⁸ , ³⁰ . The results of our study, with a dosing interval of 10 h and approximately a 90% reduction in dasatinib plasma exposure, underlines the importance of the time interval between PPI and crystalline dasatinib dosing to adequately quantitate the impact on GI absorption and bioavailability. The reduced bioavailability of dasatinib when comedicated is clinically relevant as dasatinib exposure has been linked to cytogenetic and major molecular response (MMR). Albeit there is a paucity of PK–PD data from prospective clinical trials, AUC, and C_max thresholds for achieving MMR have been proposed at 336.1 h·ng/mL and 69.2 ng/mL. ²² Plasma exposure of dasatinib plasma following omeprazole comedication in our study resulted in an AUC and C_max of 90.6 h·ng/mL and 8.0 ng/mL, respectively. These PK parameters are substantially below the suggested thresholds for MMR and translate to a high risk of disease progression.

Our findings are relevant as a significant number of CML patients are comedicated with PPIs and TKIs. Approximately 20%‐25% of CML patients are prescribed an PPI and TKI concomitantly and as many as 30% are predicted to use PPIs at the same time as dasatinib. ⁴⁰ , ⁴¹ , ⁴² Interestingly, the prescription of the TKI and PPI appears in two thirds of cases to be by different physicians. ⁴³ Additionally, the use of TKIs and PPIs is most likely underestimated as “over the counter” use of PPIs is expected to be substantial. ⁴⁴ , ⁴⁵

Our study was conducted according to guidelines for DDI studies but does not come without limitations; healthy male participants where studied which might influence the generalizability of the results to the real‐world situation. However, the harmonized population in our study makes it possible to compare with historical data and conclude that the timing of concomitant crystalline dasatinib and PPI intake has a significant impact on the DDI. Further, clinically relevant differences of the TKI–PPI DDI between genders are not expected, due to the lack of pH differences in the proximal GI tract between men and women. ⁴⁶ , ⁴⁷ Lastly, the magnitude of the DDI is unethical to investigate in CML patients as the reduced bioavailability might lead to disease progression and jeopardize patient well‐being. The influence of timing on the magnitude of the DDI is though not expected to be different in CML patients compared to healthy subjects as the physiology on the GI tract is similar unless patients suffer from serious GI disorders.

Pharmaceutical formulation techniques, such as amorphous solid dispersion (ASD) and anhydrate formulations have been put forward to develop less pH‐sensitive forms of oral dasatinib products, allowing for comedication with all classes of ARAs. ³⁹ , ⁴⁸ , ⁴⁹ However, in two of the three medicinal products, the PPI effect has only been investigated under moderate gastric pH effect, that is, at 22 h dose interval between the PPI and dasatinib intake or not at steady state of the PPI. ³⁹ , ⁵⁰ Therefore, challenges remain to uphold the absorption rate with these two formulations which is reflected in the equality of dose between the original crystalline dasatinib and the two re‐formulated drugs. ³⁹ , ⁴⁸ A third ASD formulation of dasatinib, XS004, has been investigated at dose intervals of 9 hrs (near maximum DDI effect) between PPI (at steady state) and ASD‐dasatinib dosing, showing only minimal and clinically insignificant impact on GI absorption and bioavailability. ⁴² , ⁴⁹ Additionally, XS004 is bioequivalent at 30% lower doses and has substantially lower PK variability compared to the original crystalline dasatinib, substantiating that improved formulations can achieve improved pharmacokinetic properties such as lower pH sensitivity and higher as well as less variable bioavailability, allowing for concomitant use of PPIs. ⁴² , ⁴⁹

In conclusion, the absorption of pH‐sensitive oral drugs must be investigated at the full therapeutic effect of ARAs to evaluate the maximal effect on pharmacokinetics of comedication. Further our results highlight that the design of DDI studies must be carefully considered and be clinically relevant in order to assess the risk in clinical practice. The use of co‐administered drugs, such as PPIs, significantly impacts the exposure and efficacy of PKIs/TKIs, which might lead to impaired clinical outcomes.

Discovering and developing alternative formulations for oral drug delivery, such as ASDs, with pH‐independent and improved bioavailability, reduced intra‐ and interindividual variability, is a valid strategy allowing for comedication with ARAs and may optimize the pharmacodynamics and therapeutic response to TKIs in general.

Author Contributions

Hans Lennernäs and Magnus Brisander: Conceptualization, methodology, validation, formal analysis, investigation, data curation, writing—original draft, writing—review and editing, visualization. Charlotta Liljebris and Gérald Jesson: Methodology, investigation, data curation, writing—review and editing. Per Andersson: Conceptualization, supervision, writing—review and editing.

Funding

This work was supported by Xspray Pharma.

Conflicts of Interest

Magnus Brisander reports consultancy and equity for Xspray. Hans Lennernäs is a consultant for Xspray and Vicore, holds equity for Xspray, Astra Zeneca, Novo Nordisk, Medivir, Pfizer, Biontech, Nanologica, and LIDDS, and receives research funding from Abbvie (US) and Astra Zeneca. Per Andersson, Gérald Jesson, and Charlotta Liljebris are employees of Xspray and hold equity in Xspray.

Supporting information

Supporting Information

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.