The pharmacokinetics of oral trazpiroben (TAK‐906) after organic anion transporting polypeptide 1B1/1B3 inhibition: A phase I,randomized study

Trazpiroben is a dopamine D₂/D₃ receptor antagonist under development for the treatment of gastroparesis. This phase I, open‐label, randomized, two‐way crossover study ({"type":"clinical-trial","attrs":{"text":"NCT04121078","term_id":"NCT04121078"}}NCT04121078) evaluated the effect of single‐dose intravenous rifampin, a potent inhibitor of the organic anion transporting polypeptides (OATPs) 1B1 and 1B3, on the pharmacokinetics and safety of trazpiroben in healthy adults. The utility of coproporphyrin (CP) I and CPIII as biomarkers of OATP inhibition was also assessed. Overall, 12 participants were enrolled and randomized (1:1) into one of two treatment sequences (AB and BA). Participants received either a single oral dose of trazpiroben 25 mg (treatment A) or a single oral dose of trazpiroben 25 mg immediately after a single 30‐min intravenous infusion of rifampin 600 mg (treatment B). After a washout period of at least 7 days, participants received the other treatment. Geometric mean area under the curve from time 0 extrapolated to infinity (AUC_∞) and maximum serum concentration (C _max) of plasma trazpiroben were higher in participants receiving treatment B than those receiving treatment A (AUC_∞, 168.5 vs. 32.68 ng*h/ml; C _max, 89.62 vs. 14.37 ng/ml); corresponding geometric mean ratios (90% confidence interval) showed 5.16 (4.25–6.25) and 6.24 (4.62–8.42)‐fold increases in these parameters, respectively. In this study, trazpiroben was confirmed as a substrate of OATP1B1/1B3, and therefore co‐administration of trazpiroben with moderate to strong inhibitors of OATP1B1/1B3 is not recommended. This is also the first assessment of the utility of CPI and CPIII as endogenous biomarkers of OATP1B1/1B3 inhibition after a single intravenous dose of rifampin.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Despite the disease burden of gastroparesis, treatment options remain limited. Affected patients are often treated for multiple comorbidities, along with receiving medication for symptomatic management of gastroparesis, making polypharmacy a common issue. Consequently, the potential for drug–drug interactions (DDIs) must be considered when developing new treatments for this disease.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of a single intravenous dose of rifampin, an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor, on the single‐dose pharmacokinetics of oral trazpiroben in healthy adults and explored the use of coproporphyrin (CP) I and CPIII as endogenous biomarkers of OATP1B1/1B3 activity.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study confirms trazpiroben as an OATP1B1/1B3 substrate, and is the first exploring the utility of CPI and CPIII as endogenous biomarkers to assess clinical OATPIB1/1B3‐mediated DDIs after intravenous rifampin administration.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Co‐administration of trazpiroben with moderate to strong OATP1B1/1B3 inhibitors is not recommended. CPI and CPIII may be suitable biomarkers for assessing OATP1B1/1B3‐mediated DDIs after administering single‐dose intravenous rifampin.     

Evaluation of the potential for pharmacokinetic interaction between tirabrutinib and levonorgestrel/ethinyl estradiol in healthy female volunteers

Tirabrutinib (TIRA), a potent and nonreversible oral Bruton tyrosine kinase inhibitor, is evaluated for treatment of certain hematological malignancies and inflammatory diseases. A drug–drug interaction study to evaluate the effect of TIRA on the pharmacokinetics of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted in healthy female participants (N = 26). Participants received a single dose of LEVO (150 mcg)/EE (30 mcg) alone (reference), and on day 12 of a 15‐day regimen of TIRA 160 mg once‐daily (test). Intensive blood sampling for determination of LEVO, EE, and TIRA plasma concentrations was conducted, and safety was assessed throughout the study. Pharmacokinetic interactions were evaluated using 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of the test versus reference treatments. The GLSM (90% CI) ratios of area under the concentration‐time curve from zero to infinity (AUC_inf; LEVO: 0.95, 95% CI: 0.88–1.03, EE: 1.10, 95% CI: 1.05–1.16) and maximum plasma concentration (C_max; LEVO: 0.85, 95% CI: 0.74–0.98, EE: 1.07, 95% CI: 0.98–1.18) were within the prespecified 0.70 to 1.43 no effect bounds; and the AUC ratios met the stricter 0.80 to 1.25 equivalence bounds. Study treatments were generally well‐tolerated. In conclusion, co‐administration with TIRA did not alter the exposure of LEVO/EE, and accordingly LEVO/EE containing oral contraceptives can serve as a contraception method for participants on TIRA 160 mg (or lower) daily doses.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Tirabrutinib (TIRA) is a Bruton tyrosine kinase inhibitor developed for treatment of certain hematological malignancies and inflammatory diseases. Due to teratogenic potential of TIRA, enrollment of women of childbearing age is contingent upon the use of highly effective contraception.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study evaluated the potential effect of TIRA 160 mg once‐daily regimen on the exposure of a hormonal oral contraceptive containing levonorgestrel (LEVO) and ethinyl estradiol (EE).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

TIRA 160 mg once daily did not have any clinically relevant impact on the exposures of LEVO and EE.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Combination oral contraception containing LEVO and EE can be allowed as a highly effective form of contraception during administration of TIRA at 160 mg once daily or lower daily doses.     

Phase I study in healthy participants to evaluate safety,tolerability, and pharmacokinetics of inhaled nezulcitinib,a potential treatment for COVID‐19

Nezulcitinib (TD‐0903), a lung‐selective pan–Janus‐associated kinase (JAK) inhibitor designed for inhaled delivery, is under development for treatment of acute lung injury associated with coronavirus disease 2019 (COVID‐19). This two‐part, double‐blind, randomized, placebo‐controlled, single ascending dose (part A) and multiple ascending dose (part B) phase I study evaluated the safety, tolerability, and pharmacokinetics (PK) of nezulcitinib in healthy participants. Part A included three cohorts randomized 6:2 to receive a single inhaled dose of nezulcitinib (1, 3, or 10 mg) or matching placebo. Part B included three cohorts randomized 8:2 to receive inhaled nezulcitinib (1, 3, or 10 mg) or matching placebo for 7 days. The primary outcome was nezulcitinib safety and tolerability assessed from treatment‐emergent adverse events (TEAEs). The secondary outcome was nezulcitinib PK. All participants completed the study. All TEAEs were mild or moderate in severity, and none led to treatment discontinuation. Overall (area under the plasma concentration‐time curve) and peak (maximal plasma concentration) plasma exposures of nezulcitinib were low and increased in a dose‐proportional manner from 1 to 10 mg in both parts, with no suggestion of clinically meaningful drug accumulation. Maximal plasma exposures were below levels expected to result in systemic target engagement, consistent with a lung‐selective profile. No reductions in natural killer cell counts were observed, consistent with the lack of a systemic pharmacological effect and the observed PK. In summary, single and multiple doses of inhaled nezulcitinib at 1, 3, and 10 mg were well‐tolerated in healthy participants, with dose‐proportional PK supporting once‐daily administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

There are a number of investigations of orally delivered Janus‐associated kinase (JAK) inhibitors for the treatment of coronavirus disease 2019 (COVID‐19)–associated cytokine storm. The systemic JAK inhibitor baricitinib appears to be effective for treatment of COVID‐19. An inhaled pan‐JAK inhibitor for local delivery to the lung, nezulcitinib, was in preclinical development at the start of the COVID‐19 pandemic but had not yet been tested in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This first‐in‐human study addresses the safety and pharmacokinetics (PK) of nezulcitinib in healthy participants, and the appropriateness to move nezulcitinib forward in clinical trials in patients with COVID‐19 infection.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Nezulcitinib was generally well‐tolerated in healthy participants; adverse events were mild or moderate in severity, and none resulted in study discontinuation. The PK of nezulcitinib were consistent with preclinical results suggesting a lung‐selective profile and support once‐daily dosing.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results informed an ongoing phase II clinical trial of nezulcitinib for treatment of acute lung injury associated with COVID‐19 in symptomatic patients ({"type":"clinical-trial","attrs":{"text":"NCT04402866","term_id":"NCT04402866"}}NCT04402866).     

Evaluation of drug‐drug interaction potential between omecamtiv mecarbil and rosuvastatin,a BCRP substrate,with a clinical study in healthy subjects and using a physiologically‐based pharmacokinetic model

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmacokinetic (PK) drug‐drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open‐label study in 14 healthy subjects. The ratios of the geometric least‐square means (90% confidence intervals [CIs]) of rosuvastatin co‐administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8–141.9), 132.8% (90% CI 120.7–146.1), and 154.2% (90% CI 132.8–179.1) for area under the plasma‐concentration time curve from time zero to infinity (AUC_inf), area under the plasma‐concentration time curve from time zero to time of last quantifiable concentration (AUC_last), and maximum observed plasma concentration (C_max), respectively. Whereas the DDI study with rosuvastatin was conducted with the co‐administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically‐based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUC_inf and C_max were 1.18 (90% CI 1.16–1.20) and 2.04 (90% CI 1.99–2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Omecamtiv mecarbil (OM) is a cardiac myosin activator and is currently under investigation for the treatment of heart failure with reduced ejection fraction.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the drug‐drug interaction (DDI) potential of OM on the pharmacokinetics of rosuvastatin, a BCRP substrate, using a clinical study and a physiologically‐based pharmacokinetic (PBPK) modeling approach.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The clinical study and PBPK modeling analyses confirm that OM is expected to be a weak inhibitor of BCRP in the clinical setting.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study highlights the DDI potential of single doses of OM for BCRP substrates from a clinical study and demonstrates the importance of the PBPK modeling approach to investigate DDI effects following multiple doses of OM at therapeutic concentrations.     

Effect of cenobamate on the single‐dose pharmacokinetics of multiple cytochrome P450 probes using a cocktail approach in healthy subjects

This study was designed to evaluate the effects of cenobamate, an antiseizure medication for focal seizures, on the pharmacokinetics of cytochrome P450 probes (bupropion, CYP2B6; midazolam, CYP3A4/5; warfarin, CYP2C9; and omeprazole, CYP2C19) in healthy subjects. Probes were administered alone on days 1 (bupropion) and 7 (midazolam/warfarin/omeprazole), and with cenobamate 100 mg/day on day 69 (midazolam) and cenobamate 200 mg/day on days 99 (bupropion) and 105 (midazolam/warfarin/omeprazole). No significant interaction was concluded if 90% confidence intervals (CIs) for geometric mean ratios (GMRs) for area under the curve (AUC) and maximum concentration of CYP substrates and/or their metabolites were within the no‐effect interval (0.80–1.25). When co‐administered with cenobamate 100 mg/day, AUC from time of administration up to the time of the last quantifiable concentration (AUC_0–last) GMR (90% CIs) for midazolam was 0.734 (0.647–0.832). When co‐administered with cenobamate 200 mg/day, AUC_0–last GMRs (90% CI) for midazolam, bupropion, S‐warfarin, and omeprazole were 0.277 (0.238–0.323), 0.615 (0.522–0.724), 1.14 (1.10–1.18), and 2.07 (1.44–2.98), respectively. Co‐administration of cenobamate with midazolam and bupropion probes led to values that were outside and below the no effect boundary, indicating that cenobamate induces the CYP3A4/5 and CYP2B6 enzymes. Co‐administration of cenobamate led to omeprazole values which were outside and above the no‐effect boundary, but with high variability, suggesting that cenobamate may moderately inhibit CYP2C19 activity. No effect on CYP2C9 was observed with the cenobamate and warfarin combination. Co‐administration of cenobamate with these probes drugs was well‐tolerated. In this study, 200 mg/day cenobamate moderately induced CYP3A4/5 (dose‐dependently; 100 mg/day was a weak inducer), was a weak inducer of CYP2B6, moderately inhibited CYP2C19, and had a negligible effect on CYP2C9.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug‐drug interactions are a challenging aspect of managing epilepsy because many antiseizure medications (ASMs) induce or inhibit CYP450 enzymes, which are commonly involved in drug metabolism of many ASMs. Previous studies suggest that cenobamate, a US Food and Drug Administration (FDA)‐approved ASM for the treatment of adults with focal seizures, may affect the activity of certain CYP450 enzymes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study was designed to determine the effects of cenobamate on the pharmacokinetics of drugs known to affect the activity of these CYP450 enzymes, known as probe drugs. These probe drugs include bupropion, (CYP2B6), midazolam (CYP3A4/5), warfarin (CYP2C9), and omeprazole (CYP2C19).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The results of this study indicate that cenobamate induces CYP2B6 activity, exhibits a dose‐dependent induction of CYP3A4/5 activity, inhibits CYP2C19 activity, and has a negligible effect on CYP2C9 activity.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These findings suggest that dose adjustments may be required when agents metabolized through these CYP450 pathways are used in conjunction with cenobamate.     

Effect of enzalutamide on PK of P‐gp and BCRP substrates in cancer patients: CYP450 induction may not always predict overall effect on transporters

Drug‐drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P‐glycoprotein [P‐gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration‐resistant prostate cancer (mCRPC). This was a phase I, open‐label, fixed‐sequence, crossover study ({"type":"clinical-trial","attrs":{"text":"NCT04094519","term_id":"NCT04094519"}}NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo‐to‐match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (C_max), area under the concentration‐time curve from the time of dosing to the last measurable concentration (AUC_last), and AUC from the time of dosing extrapolated to time infinity (AUC_inf). Secondary end points were enzalutamide and N‐desmethyl enzalutamide (metabolite) plasma C_max, AUC during a dosing interval, where tau is the length of the dosing interval (AUC_tau), and concentration immediately prior to dosing at multiple dosing (C_trough). When administered with enzalutamide, there was a 17% increase in C_max, 29% increase in AUC_last, and 33% increase in AUC_inf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a “mild” inhibitor of P‐gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N‐desmethyl enzalutamide were in agreement with previously reported data. The potential for transporter‐mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant administration of enzalutamide with medications that are substrates for P‐gp and BCRP does not require dose adjustment in this patient population.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Enzalutamide is strong inducer of CYP3A4. Preclinical data have demonstrated that enzalutamide and its active metabolite, N‐desmethyl enzalutamide, have the potential to inhibit the efflux transporters P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP).

• WHAT QUESTION DID THIS STUDY ADDRESS?

This clinical study evaluated the net inhibition and induction effect of enzalutamide on the pharmacokinetics (PK) of a transporter probe cocktail containing the P‐gp and BCRP substrates, digoxin and rosuvastatin, in men with metastatic castration‐resistant prostate cancer.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Concomitant administration with enzalutamide resulted in an increase in digoxin exposure, suggesting that enzalutamide is a “mild” inhibitor of P‐gp. No PK interaction was observed between enzalutamide and rosuvastatin, suggesting that enzalutamide has “no effect” on BCRP.

• HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Induction of CYP3A4 does not necessarily correlate with clinical effect on P‐gp and BCRP transporters. These findings are beneficial to guide future treatment recommendations, whereby concomitant administration of enzalutamide with medications that are P‐gp and BCRP substrates does not require dose adjustment.     

Effect of food on capsule and granule formulations of selumetinib

Selumetinib is an oral, potent, and highly selective allosteric MEK1/2 inhibitor approved for the treatment of pediatric patients (aged ≥2 years) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. A granule formulation of selumetinib is under development to improve dosing precision for younger pediatric patients who may be unable to swallow capsules. This phase I crossover study investigated the effect of food on the pharmacokinetic (PK) properties of selumetinib capsule and granule formulations. Healthy male volunteers were randomized to receive selumetinib granules (25 mg) or capsules (50 mg [2 × 25 mg]) under fasted or fed conditions (a low‐fat meal). Plasma concentrations and PK parameters were determined less than or equal to 48 h postdose. Safety and tolerability were assessed. Across 24 volunteers, selumetinib was absorbed quickly, with a time to maximum concentration (T_max) ranging from ~1–3 h. Geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (C_max) in the fed versus fasted state were 0.61 (90% CI 0.51–0.72) and 0.40 (90% CI 0.33–0.48) for the granule and capsule formulations, respectively, whereas geometric mean ratios (90% CI) for area under the plasma drug concentration‐time curve in the fed versus fasted state were 0.97 (90% CI 0.91–1.02) and 0.62 (90% CI 0.55–0.70), respectively. Levels of less than 10% conversion to the N‐desmethyl selumetinib metabolite were observed. Selumetinib was well‐tolerated, with only a few adverse events of mild intensity reported. Selumetinib administration with a low‐fat meal resulted in lower C_max and longer T_max for both formulations versus fasted conditions. However, area under the curve for selumetinib granules was similar under fasted and fed conditions. Overall, these findings support further development of this formulation for pediatric patients.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selumetinib is approved for use in pediatric patients with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. A granule formulation is under development to improve dosing precision and swallowability for younger pediatric patients who may be unable to swallow capsules.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the effect of food on the pharmacokinetic properties of selumetinib capsule and granule formulations in healthy male volunteers to assess whether food restrictions may be needed with administration of the granule formulation.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Absorption of selumetinib was prolonged in the fed state compared with the fasted state for both capsule and granule formulations, as determined by a lower maximum plasma concentration (C_max) and longer T_max). However, selumetinib granules had a similar exposure (AUC) in both fasted and fed conditions, suggesting that the rate of absorption may be affected, but not to the extent of absorption with food. Furthermore, similarities observed in AUC between the granule and capsule formulations suggest that the granule formulation can be used in a similar setting to the capsule.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These data support further clinical development of the selumetinib granule formulation for pediatric patients.     

Vericiguat in combination with isosorbide mononitrate in patients with chronic coronary syndromes: The randomized,phase Ib,VISOR study

Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long‐acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co‐administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double‐blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co‐administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty‐five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline‐ and placebo‐adjusted vital signs showed reductions of 1.4–5.1 mmHg (systolic blood pressure) and 0.4–2.9 mmHg (diastolic blood pressure) and increases of 0.0–1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose‐dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well‐tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Vericiguat is indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following a hospitalization for HF or need for outpatient intravenous diuretics, in adults with symptomatic chronic HF and ejection fraction less than 45%.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the impact of co‐administration of vericiguat and long‐acting nitrates. The combination of vericiguat with isosorbide mononitrate was generally well‐tolerated, and the adverse event profile was in line with the mode of action of both drugs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

There is limited experience with vericiguat in combination with long‐acting nitrates and these data provide information to guide prescribers.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These data support that there is no clinically relevant pharmacodynamic interaction between vericiguat and the long‐acting nitrate isosorbide mononitrate in patients with chronic coronary syndromes.     

Pharmacokinetics of asciminib in the presence of CYP3A or P‐gp inhibitors,CYP3A inducers,and acid‐reducing agents

Asciminib is a first‐in‐class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P‐glycoprotein (P‐gp) and possesses pH‐dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P‐gp inhibitors, CYP3A inducers and acid‐reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (C_max) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40‐fold excess to itraconazole] in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13–15%) and the strong P‐gp inhibitor quinidine (by ~13–16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in C_max. The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P‐gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin‐containing drug formulations.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Asciminib is a first‐in‐class BCR::ABL1 inhibitor, specifically targeting the ABL myristoyl pocket, and a substrate of CYP3A4 and P‐gp. Asciminib displays pH‐dependent solubility in aqueous solution.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study explored the drug–drug interaction risk of asciminib as a victim with CYP3A inhibitors, CYP3A inducers, P‐gp inhibitors, and acid‐reducing agents (ARAs).

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Asciminib as a victim was weakly affected by concomitantly administered P‐gp inhibitors, strong CYP3A inhibitors, strong CYP3A inducers, or ARAs. However, a substantial effect of cyclodextrin (as an excipient in itraconazole oral solution) was observed; indirect evidence showed that cyclodextrin markedly decreased asciminib bioavailability.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results support the concomitant use of CYP3A and P‐gp inhibitors, CYP3A inducers and ARAs in patients treated with asciminib. Care should be exercised when using itraconazole oral solution or other cyclodextrin‐containing formulations in clinical studies due to their potential impact on absorption of orally co‐administered compounds.     

Peppermint oil effects on the gut microbiome in children with functional abdominal pain

Peppermint oil (PMO) is effective in the treatment of functional abdominal pain disorders, but its mechanism of action is unclear. Evidence suggests PMO has microbicidal activity. We investigated the effect of three different doses of PMO on gut microbiome composition. Thirty children (7–12 years of age) with functional abdominal pain provided a baseline stool sample prior to randomization to 180, 360, or 540 mg of enteric coated PMO (10 participants per dose). They took their respective dose of PMO (180 mg once, 180 mg twice, or 180 mg thrice daily) for 1 week, after which the stool collection was repeated. Baseline and post‐PMO stools were analyzed for microbiome composition. There was no difference in alpha diversity of the gut microbiome between the baseline and post‐PMO treatment. Principal coordinate analysis revealed no significant difference in overall bacterial composition between baseline and post‐PMO samples, as well as between the PMO dose groups. However, the very low abundant Collinsella genus and three operational taxonomic units (one belonging to Collinsella) were significantly different in samples before and after PMO treatment. The Firmicutes/Bacteroidetes ratio was lower in children who received 540 mg of PMO compared to the 180 mg and 360 mg dose groups (p = 0.04). Network analysis revealed separation between pre‐ and post‐PMO fecal samples with the genus Collinsella driving the post‐PMO clusters. PMO administration appeared to impact only low abundance bacteria. The 540 mg PMO dose differentially impacted the Firmicutes/Bacteroidetes ratio. A higher dose and/or longer duration of treatment might yield different results.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Peppermint oil (PMO) is used commonly to treat gut disorders. In vitro PMO can be bactericidal.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does oral administration of PMO impact gut microbiome composition? Is there a dose‐response impact on gut microbiome composition?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

PMO at the doses tested can impact gut microbiome composition. The highest dose of PMO (540 mg) changed the Firmicutes/Bacteroidetes ratio.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Some of the clinical benefit of PMO may be mediated through a change in gut microbiome composition. Higher doses and/or longer treatment should be tested to evaluate the impact on gut microbiome composition.     

Evaluation of the safety,tolerability, and pharmacokinetics of RO7049389 in healthy Chinese volunteers

The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics (PKs) of RO7049389 in healthy Chinese volunteers (HVs) and evaluate potential ethnic differences in the safety and PKs using data from this study and the first‐in‐human study (in which most of the HVs were non‐Asian). HVs randomly received a single dose of 200–600 mg of RO7049389 or a placebo in a single ascending dose (n = 28) or multiple doses of 200–400 mg of RO7049389 or a placebo in multiple ascending doses (n = 24). Safety and tolerability were monitored throughout the study. Serial blood samples were collected for PK analysis. RO7049389 was safe and well‐tolerated in the HVs. The time to maximum concentration ranged from 1.5 to 3.0 h, and terminal half‐life ranged from 3.66 to 14.6 h. A single dose of 200–600 mg and multiple doses of 200–400 mg exhibited nonlinear PKs. In general, the safety profiles were comparable between non‐Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non‐Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

RO7049389 is a small molecule that is being developed as an orally administered solid dosage formulation for the treatment of chronic hepatitis B infection. The healthy volunteers (HVs) part of the first‐in‐human study of RO7049389 was completed at the time the first volunteer of this study was enrolled.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics of RO7049389 in Chinese HVs and evaluate potential ethnic differences between Chinese and non‐Asians.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

In general, the safety profiles were comparable between non‐Asian and Chinese HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non‐Asian HVs. The higher exposure might be due to the liver uptake of RO7049389 by OATP1B.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus infection.     

Safety,tolerability, and pharmacokinetics of oral baicalein tablets in healthy Chinese subjects: A single‐center,randomized, double‐blind,placebo‐controlled multiple‐ascending‐dose study

Baicalein is a biologically important flavonoid in extracted from the Scutellaria baicalensis Georgi, which can effectively inhibit the influenza virus. This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials. In this multiple‐ascending‐dose placebo‐controlled trial, 36 healthy subjects were randomized to receive 200, 400, and 600 mg of baicalein tablet or placebo once daily on day 1 and day 10, 3 times daily on days 4–9. All groups were intended to produce safety and tolerability outcomes (lowest dose first). Blood and urine samples were collected from subjects in the 600 mg group for baicalein PK analysis. Our study had shown that Baicalein tablet was generally safe and well‐tolerated. All adverse events were mild and resolved without any intervention except one case of fever reported in the 600 mg group, which was considered as moderate but not related with baicalein as judged by the investigator. Oral baicalein tablets were rapidly absorbed with peak plasma levels being reached within 2 h after multiple administration. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many studies have shown that baicalin has an anti‐influenza effect in cell and animal experiments. The primary mechanism of action is that baicalein has a strong inhibitory effect on the sialidase of the influenza virus.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study aimed to analyze the safety and pharmacokinetic (PK) characteristics of baicalein tablets in healthy Chinese subjects and provide more information for phase II clinical trials.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our study results have shown that baicalein tablets were administered multiple times within the studied dose range were safe and well‐tolerated in healthy Chinese subjects with no serious or severe adverse effects. The highest urinary excretion of baicalein and its metabolites peaked in 2 h, followed by 12 h, with a double peak trend. Oral baicalein tablets were rapidly absorbed with peak plasma levels reached within 2 h after multiple administration.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study addresses the safety outcomes of baicalein tablets and emphasizes the PKs of baicalein, which provides a better understanding and a scientific basis of the clinical application of baicalein for further evaluation.     

A phase I,first‐in‐human,randomized dose‐escalation study of anti‐activated factor XII monoclonal antibody garadacimab

Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single‐center, first‐in‐human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow‐up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty‐eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment‐emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose‐dependent manner. Sustained inhibition of FXIIa‐mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose‐dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single‐dose i.v. and s.c.) was well‐tolerated in healthy volunteers. Dose‐dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID‐19).

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Plasma protein factor XII (FXII) is the principal initiator of the contact system. Activated FXII (FXIIa) leads to the production of the proinflammatory mediator bradykinin via the kallikrein–kinin system. The production of bradykinin results in increased vascular permeability, vasodilation, and chemotaxis. FXIIa is being investigated as a potential target in hereditary angioedema. Garadacimab is a fully human recombinant antibody that specifically inhibits FXIIa. Preclinical in vitro and in vivo studies of garadacimab showed it to inhibit FXIIa, produce anti‐inflammatory effects, and prevent the formation of bradykinin as well as effectively reduce edema and block proinflammatory cytokine production.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I, single‐center study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating doses of garadacimab after a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The data in this study show that s.c. and i.v. administration of garadacimab in healthy male volunteers is well‐tolerated with no serious treatment‐emergent adverse events (TEAEs) reported during the study, and no discontinuations of garadacimab due to TEAEs. Moreover, the data show that garadacimab plasma concentrations and inhibition of FXII‐mediated kallikrein activity were increased in a dose‐dependent manner. A dose‐dependent increase in activated partial thromboplastin time with no change in prothrombin time and no associated bleeding was also observed.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study provides the first evidence of the safety and pharmacodynamic impact in FXIIa blockade in humans using a monoclonal antibody. These results support the investigation of garadacimab in a variety of disease states.     

Efficacy of add‐on therapy with intravenous immunoglobulin in steroid hyporesponsive DRESS syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, potentially life‐threatening, delayed, drug‐induced hypersensitivity reaction. Immediate withdrawal of the culprit drug and administration of systemic corticosteroids is the most widely accepted treatment. However, it is difficult to manage patients with DRESS syndrome who are not responsive to systemic steroids. We studied the efficacy of intravenous immunoglobulins (IVIGs) in patients with DRESS syndrome unresponsive to systemic steroids. We retrospectively reviewed patients with DRESS syndrome who received IVIG in addition to systemic steroids during 2012–2017 and compared the clinical features and course of DRESS syndrome, before and after IVIG treatment. Eighteen DRESS patients (9 men) were included. The most frequent offending drugs were dapsone in five patients, followed by vancomycin in three patients, and carbamazepine in three patients. Rash, fever, lymphadenopathy, atypical lymphocytes, and hepatic involvement were common clinical findings. IVIG treatment was added within a median time of 7 days from the commencement of systemic steroid therapy. After IVIG treatment (total dosage: 1–2 g/kg), the fever resolved within a median time of 1 day (range, 0–3) and liver enzymes improved substantially within a median time of 13 days (range, 0–27). No severe adverse reactions related to IVIG therapy were observed in this study; however, there was one case of mortality. The addition of IVIG in DRESS syndrome in cases refractory to systemic steroid treatment may be helpful in hastening recovery. However, comparative studies using a placebo group are needed.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe delayed drug reaction. The main treatment is administration of systemic steroids. However, treatment of steroid hyporesponsive adults is unclear.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We studied the efficacy of intravenous immunoglobulins (IVIGs) in patients with DRESS syndrome unresponsive to systemic steroids.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We describe cases of adults with steroid hyporesponsive DRESS syndrome who were successfully treated with add‐on IVIG therapy with systemic steroids with minimal side effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our results show the benefits of IVIG add‐on treatment with systemic steroids in steroid hyporesponsive DRESS syndrome, and suggest pretreatment medication may result in fewer side effects.     

Relationship of hemoglobin level and plasma coproporphyrin‐I concentrations as an endogenous probe for phenotyping OATP1B

Plasma coproporphyrin‐I (CP‐I) concentration is used as a sensitive and selective endogenous probe for phenotyping organic anion transporting polypeptides 1B (OATP1B) activity in many studies. CP‐I is produced in the process of heme synthesis, but the relationship between plasma CP‐I concentrations and heme synthesis activity is unknown. In this study, we evaluated the relationship between plasma CP‐I concentration and hemoglobin level as a biomarker of heme synthesis activity. The data of 391 subjects selected from the Japanese general population were analyzed. One hundred twenty‐six participants had OATP1B1*15 allele, 11 of whom were homozygous (OATP1B1*15/*15). Multiple regression analysis identified hemoglobin level as an independent variable associated with plasma CP‐I concentration (p < 0.0001). A significant positive correlation was observed between hemoglobin level and plasma CP‐I concentration in participants without OATP1B1*15 allele (n = 265; r _s = 0.35, p < 0.0001) and with OATP1B1*15 allele (n = 126; r _s =0.27, p = 0.0022). However, Kruskal–Wallis test showed no large difference in Kruskal–Wallis statistics between the distribution of plasma CP‐I concentrations and that of ratio of plasma CP‐I to hemoglobin among six OATP1B1 polymorphism groups. These findings suggest that the hemoglobin level seems to reflect biosynthesis of CP‐I. However, correction by hemoglobin level is not required when using basal plasma CP‐I concentration for phenotyping OATP1B activity.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Coproporphyrin‐I (CP‐I) in plasma is a sensitive and specific endogenous biomarker for phenotyping organic anion transporting polypeptides 1B (OATP1B), and has been used for phenotyping OATP1B activity, such as in clinical drug‐drug interaction studies. CP‐I is produced during the process of heme synthesis, indicating that correction of plasma CP‐I concentration by hemoglobin level as an indicator of heme synthesis activity may be needed.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Does correction by hemoglobin level improve the usefulness of CP‐I as a probe for OATP1B phenotyping?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Hemoglobin level was identified as an independent variable associated with plasma CP‐I concentrations. However, no large difference in Kruskal–Wallis statistics was observed between the distribution of plasma CP‐I concentrations and that of CP‐I/Hb ratio among six OATP1B1 polymorphism groups.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Hemoglobin level seems to reflect biosynthesis of CP‐I. However, correction by hemoglobin level is not needed when using plasma CP‐I concentration for phenotyping OATP1B activity.     

Single‐dose of LC51‐0255, a selective S1P1 receptor modulator,showed dose‐dependent and reversible reduction of absolute lymphocyte count in humans

Reducing the peripheral absolute lymphocyte count (ALC) is a promising therapeutic approach in treating autoimmune diseases. LC51‐0255 is a sphingosine‐1‐phosphate 1 receptor modulator, which is known to decrease the peripheral ALC. We aimed to assess the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability profiles of LC51‐0255 after a single oral administration in healthy subjects. A randomized, double‐blind, placebo‐controlled, dose‐escalation study was conducted in 50 healthy subjects. Each subject orally received LC51‐0255 (0.25, 0.5, 1, 2, or 4 mg) or its matching placebo in an 8:2 ratio. Blood and urine samples were collected to assess the PKs, and PDs was evaluated using peripheral ALC and 24‐h hourly heart rate data. Safety and tolerability were assessed by monitoring treatment emergent adverse events (TEAEs), vital signs, 12‐lead electrocardiogram (ECG), continuous 24‐h ECG (via Holter monitoring), clinical laboratory tests, ophthalmologic tests, pulmonary function tests, and physical examinations. A single dose of LC51‐0255 reduced ALC and heart rate in a reversible and dose‐dependent manner. Systemic exposure of LC51‐0255 increased dose‐dependently and its half‐life ranged from 72.2 to 134.0 h. ALC and the systemic exposure of LC51‐0255 seemed to be negatively correlated. LC51‐0255 was well‐tolerated up to 2 mg, and the most common TEAE was bradycardia. The results of this study suggest that LC51‐0255 can be developed into a beneficial treatment option for autoimmune disease.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Reducing the peripheral absolute lymphocyte count (ALC) is a promising therapeutic approach to treat autoimmune diseases. Sphingosine‐1‐phosphate 1 (S1P₁) receptor modulator reduces peripheral ALC by preventing the recirculation of lymphocytes from lymphatic tissue to target organs.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We performed this study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability profiles of LC51‐0255, a novel S1P₁ receptor modulator, in humans.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Our results showed that LC51‐0255 has a relatively long half‐life, is well‐tolerated, and reduces ALC in a dose‐dependent and reversible manner.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our results provide evidence that a single dose of LC51‐0255 can be further developed into a beneficial treatment option for patients with autoimmune disease.     

No implication of HIV coinfection on the plasma exposure to rifampicin,pyrazinamide, and ethambutol in tuberculosis patients

There are contrasting findings regarding the effect of HIV on the pharmacokinetics of first‐line anti‐tubercular drugs (FLATDs) due to a lack of prospective controlled clinical studies, including patients with tuberculosis (TB) and patients with TB living with HIV. This study aims to assess the effect of HIV coinfection and antiviral therapy on the plasma exposure to FLATDs in patients with TB. HIV negative (TB‐HIV− group; n = 15) and HIV positive (TB‐HIV+ group; n = 18) adult patients with TB were enrolled during the second month of FLATDs treatment. All TB‐HIV+ patients were on treatment with lamivudine, tenofovir (or zidovudine), and raltegravir (or efavirenz). Serial blood sampling was collected over 24 h and FLATDs pharmacokinetic parameters were evaluated using noncompartmental methods. In the TB‐HIV+ patients, dose‐normalized plasma exposure area under the curve from zero to 24 h (nAUC_0–24; geometric mean and 95% confidence interval [CI]) values at steady‐state to rifampicin, pyrazinamide, and ethambutol were 18.38 (95% CI 13.74–24.59), 238.21 (95% CI 191.09–296.95), and 18.33 (95% CI 14.56–23.09) µg∙h/ml, respectively. Similar plasma exposure was found in the TB‐HIV− patients. The geometric mean and 90% CI of the ratios between TB‐HIV− and TB‐HIV+ groups suggest no significant pharmacokinetic interaction between the selected antivirals and FLATDs. Likewise, HIV coinfection itself does not appear to have any effect on the plasma exposure to FLATDs.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

First‐line anti‐tubercular drugs (FLATDs) plasma exposure is an important variable of tuberculosis (TB) outcome; however, there are contrasting findings regarding the effect of HIV on the pharmacokinetics of FLATDs due to a lack of prospective controlled clinical studies, including HIV positive and HIV negative patients with TB.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluates the effect of HIV coinfection on the pharmacokinetics of rifampicin, pyrazinamide, and ethambutol in patients who are on stable therapy in the second month of FLATDs treatment.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study shows no evidence that the pharmacokinetics of rifampicin, pyrazinamide, and ethambutol in patients with TB are affected by HIV coinfection or by any of the standard of care HIV comedications allowed in the study (lamivudine, zidovudine, tenofovir, efavirenz, or raltegravir).

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

HIV coinfection does not require dose adjustment of rifampicin, pyrazinamide, and ethambutol in patients with TB.     

REGN1908‐1909 monoclonal antibodies block Fel d 1 in cat allergic subjects: Translational pharmacokinetics and pharmacodynamics

REGN1908‐1909, a 1:1 cocktail of two fully human IgG₄ monoclonal antibodies (mAbs), REGN1908 and REGN1909, is being evaluated for treatment of cat allergy. Both REGN1908 and REGN1909 bind to the dominant cat allergen, Fel d 1. Adults with cat allergy confirmed by skin prick test (SPT) were randomized to single subcutaneous administration of placebo (n = 6) or REGN1908‐1909 at doses of 150 (n = 6), 300 (n = 6), or 600 mg (n = 6). Blood samples were taken at prespecified time points for pharmacokinetic (PK) analysis and exploratory evaluation of biomarkers (IgE and SPT). Safety was assessed. Drug concentration‐time profiles in serum for ascending doses of REGN1908‐1909 were consistent with linear PKs. Noncompartmental analysis showed that maximum concentration (C_max) and exposure increased proportionately with dose, with similar time to maximum concentration (T_max) for REGN1908 and REGN1909 (6.2 to 8.2 days across doses), and a longer terminal half‐life for REGN1908 (~ 30 days) relative to REGN1909 (~ 21 days). Adverse events were not dose dependent; there were no dose‐limiting toxicities. REGN1908‐1909 is characterized by linear and dose‐proportional kinetics of the two individual mAb components. A single 600 mg dose maintains total mAb mean concentrations in serum above the target (mean of ~ 10 mg/L) for 8–12 weeks. Maintaining this mean target concentration resulted in translational pharmacodynamic effects: maximal mast cell degranulation in a passive cutaneous anaphylaxis mouse model, and maintenance of clinical efficacy measured by Total Nasal Symptom Score in a previous proof‐of‐mechanism study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

REGN1908 and REGN1909 are fully human IgG₄ monoclonal antibodies that demonstrated high affinity, noncompetitive binding to distinct epitopes of Fel d 1 allergen. Whereas a cocktail of these monoclonal antibodies, REGN1908‐1909, is being evaluated as a passive immunization strategy for treatment of cat allergy, its pharmacokinetics (PKs) have not been fully characterized, especially with respect to potential pharmacodynamic (PD) effects.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This first‐in‐human study of REGN1908‐1909 evaluated the PKs and safety of REGN1908‐1909 in cat‐allergic individuals who were otherwise healthy. Translational context is provided by discussing the PK profile with regard to PD effects observed in mouse models and among patients in a proof‐of‐mechanism study.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The PK profile of subcutaneous administration of REGN1908‐1909 in subjects with cat allergy appeared to be dose‐proportional, with half‐lives of the individual components within the expected range for a typical monoclonal antibody. The concentration‐time curve was consistent with previously reported peak PD effects, including clinical response that temporally coincides with the time of peak concentrations of the drugs in serum.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE

Pharmacokinetic results support REGN1908‐1909 600 mg as the dose that maintains drug concentrations in serum above a mean target concentration required for PD effects, and suggest a prophylactic dosing regimen of every 2–3 months.     

SMAD4 loss is associated with response to neoadjuvant chemotherapy plus hydroxychloroquine in patients with pancreatic adenocarcinoma

SMAD4, a tumor suppressor gene, is lost in up to 60%–90% of pancreatic adenocarcinomas (PDAs). Loss of SMAD4 allows tumor progression by upregulating autophagy, a cell survival mechanism that counteracts apoptosis and allows intracellular recycling of macromolecules. Hydroxychloroquine (HCQ) is an autophagy inhibitor. We studied whether HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. We retrospectively analyzed the SMAD4 status of patients with PDA enrolled in two prospective clinical trials evaluating pre‐operative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ ({"type":"clinical-trial","attrs":{"text":"NCT01128296","term_id":"NCT01128296"}}NCT01128296). More recently, a randomized trial of gemcitabine/nab‐paclitaxel +/− HCQ evaluated Evans Grade histopathologic response ({"type":"clinical-trial","attrs":{"text":"NCT01978184","term_id":"NCT01978184"}}NCT01978184). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher’s exact test and log‐rank test were used to assess response and survival. Fifty‐two patients receiving HCQ with neoadjuvant chemotherapy were studied. Twenty‐five patients had SMAD4 loss (48%). 76% of HCQ‐treated patients with SMAD4 loss obtained a histopathologic response greater than or equal to 2A, compared with only 37% with SMAD4 intact (p = 0.006). Although loss of SMAD4 has been associated with worse outcomes, in the current study, loss of SMAD4 was not associated with a detriment in median overall survival in HCQ‐treated patients (34.43 months in SMAD4 loss vs. 27.27 months in SMAD4 intact, p = 0.18). The addition of HCQ to neoadjuvant chemotherapy in patients with PDA may improve treatment response in those with SMAD4 loss. Further study of the relationship among SMAD4, autophagy, and treatment outcomes in PDA is warranted.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

​ SMAD4 is depleted in 60%–90% of pancreatic adenocarcinomas (PDAs) and associated with poor prognosis. SMAD4‐deficient PDA cells are resistant to therapies by upregulating autophagy, a cell survival mechanism that allows recycling of organelles during cytotoxic stress.

• WHAT QUESTION DID THIS STUDY ADDRESS?

​This study examined clinical outcomes after autophagy inhibition with hydroxychloroquine (HCQ) in patients with PDA according to SMAD4 status. We hypothesized that patients with depleted SMAD4 would derive the greatest benefit from HCQ.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

​Patients with SMAD4 depleted PDA had a significant improvement in histopathologic response and R0 resection rates after receiving HCQ compared with patients with preserved SMAD4. When treated with HCQ, loss of SMAD4 was not associated with a detriment in median overall survival.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

​In patients with SMAD4 loss, the addition of HCQ to neoadjuvant chemotherapy is associated with improved clinical outcomes. Further study of autophagy inhibition with HCQ in PDA with SMAD4 loss is warranted. ​     

HLA variants associated with azathioprine‐induced pancreatitis in patients with Crohn’s disease

The immunosuppressant drug azathioprine is associated with a 4% risk of acute pancreatitis in patients with inflammatory bowel disease (IBD). Studies have demonstrated an increased risk in carriers of HLA‐DQA1*02:01 and HLA‐DRB1*07:01. We investigated whether these human leukocyte antigen (HLA) types were associated with azathioprine‐induced pancreatitis also in Swedish patients with IBD, and whether the type of disease affected the association. Nineteen individuals with IBD who developed acute pancreatitis after initiation of azathioprine were genotyped and compared with a population control cohort (n = 4891) and a control group matched for disease (n = 81). HLA‐DQA1*02:01 and HLA‐DRB1*07:01 were in full linkage disequilibrium, and were significantly associated with acute pancreatitis both when cases were compared with population controls (OR 3.97 [95% CI 1.57–9.97], p = 0.0035) and matched controls (OR 3.55 [95% CI 1.23–10.98], p = 0.0275). In a disease‐specific analysis, the correlation was positive in patients with Crohn''s disease versus matched controls (OR 9.27 [95% CI 1.86–46.19], p = 0.0066), but not in those with ulcerative colitis versus matched controls (OR 0.69 [95% CI 0.07–6.74], p = 0.749). In patients with Crohn''s disease, we estimated the conditional risk of carriers of HLA‐DQA1*02:01‐HLA‐DRB1*07:01 to 7.3%, and the conditional risk of a non‐carrier to 2.2%. We conclude that HLA‐DQA1*02:01‐HLA‐DRB1*07:01 is a marker for increased risk of acute pancreatitis in individuals of Swedish genetic origin, treated with azathioprine for Crohn''s disease.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

HLA‐DQA1*02:01 and HLA‐DRB1*07:01 have been shown to increase the risk of acute pancreatitis in individuals with inflammatory bowel disease (IBD) treated with azathioprine.

• WHAT QUESTION DID THIS STUDY ADDRESS?

It is unknown whether this risk also applies to patients of Swedish origin and if the risk differs depending on type of IBD.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

We show that HLA‐DQA1*02:01 and HLA‐DRB1*07:01 are risk markers for azathioprine‐induced acute pancreatitis in patients of Swedish origin. We propose that this risk could be restricted to those with Crohn''s disease, where the estimated risk equals 7.3% for carriers and 2.2% for non‐carriers.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As the HLA‐DQA1*02:01‐HLA‐DRB1*07:01 haplotype has a frequency of ~7% in the Swedish population, preemptive HLA‐typing could be useful for the selection of patients with Crohn''s disease that need intensified monitoring or for choice of a different therapy.