A phase 1 study of prasugrel in patients with sickle cell disease: pharmacokinetics and effects on ex vivo platelet reactivity

Aims

Prasugrel is a novel thienopyridine P2Y₁₂ adenosine diphosphate (ADP) receptor antagonist that inhibits ADP-mediated platelet activation and aggregation. Accordingly, it may be useful in reducing platelet-related ischaemia in sickle cell disease (SCD). Exposure to prasugrel''s active metabolite (Pras-AM) and its antiplatelet activity in SCD have not been investigated.

Methods

Thirteen adult patients with SCD and an equal number of matched healthy control subjects were studied before and after 12 days of 5.0 or 7.5 mg day⁻¹ prasugrel treatment. Platelet reactivity was assessed by light transmission aggregometry (LTA), impedance aggregometry (MEA), VerifyNow® P2Y12, vasodilator-stimulated phosphoprotein (VASP) phosphorylation and Plateletworks. Exposure to Pras-AM was also assessed.

Results

At baseline, patients with SCD showed increased platelet reactivity vs. healthy control subjects with VerifyNow (408 vs. 323 P2Y12 reaction units (PRU), respectively, P = 0.003) and MEA (106 vs. 77 area under the aggregation curve (AU.min), P = 0.002); lower platelet reactivity index with VASP flow cytometry (59 vs. 79% platelet reactivity index (PRI), P = 0.018); and no significant differences with LTA, VASP enzyme-linked immunosorbent assay or Plateletworks. Relative to baseline, prasugrel significantly reduced platelet reactivity by all assays in both populations (all P < 0.05). Prasugrel was well tolerated, with no bleeding-related events in patients with SCD. The mean concentration–time profiles of Pras-AM were comparable between healthy subjects and patients with SCD following a single 10 mg prasugrel dose and following the 12th dose of 7.5 or 5 mg prasugrel.

Conclusions

Results demonstrate that in response to prasugrel, patients with SCD and healthy subjects have similar degrees of platelet inhibition and exposure to Pras-AM, and provide a basis for further study of prasugrel in patients with SCD.     

The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects

Purpose

Prasugrel is a novel thienopyridine prodrug metabolised to an active metabolite that binds irreversibly to the platelet P2Y₁₂ receptor and inhibits adenosine diphosphate (ADP)-induced platelet aggregation. We compared prasugrel pharmacokinetics, pharmacodynamics, and tolerability in healthy Chinese, Japanese, Korean and Caucasian subjects.

Methods

In an open-label, single-centre, parallel-design study, 89 healthy subjects (25 Chinese, 20 Japanese, 22 Korean and 22 Caucasian) aged 20–65 years were given a prasugrel 60-mg loading dose (LD) followed by daily 10-mg maintenance doses (MD) for 7 days and then 5-mg MD for 10 days. Plasma concentrations of prasugrel’s active metabolite and inhibition of ADP-induced platelet aggregation (IPA) were determined.

Results

Mean exposure to prasugrel’s active metabolite in all treatment regimens was higher in each of the Asian groups than in the Caucasian group, although there was considerable overlap between individual exposure estimates in Asians and Caucasians. The mean IPA was also higher in Asians than in Caucasians following a prasugrel 60-mg LD, although the difference did not consistently achieve statistical significance. Prasugrel 10-mg or 5-mg MD produced statistically significantly higher IPA in each Asian group compared with that in the Caucasians. Prasugrel was well tolerated during the LD and MD regimens by all groups.

Conclusions

Mean exposure to the prasugrel active metabolite following prasugrel 60-mg LD and during daily 10-mg or 5-mg MD was higher in each of the Asian groups than in the Caucasian group, which resulted in greater platelet inhibition.     

Pharmacokinetics and tolerance of dehydroandrographolide succinate injection after intravenous administration in healthy Chinese volunteers

Aim:

Dehydroandrographolide succinate (DAS) is extracted from herbal medicine Andrographis paniculata (Burm f) Nees. DAS injection is used in China for the treatment of viral pneumonia and upper respiratory tract infections. The aim of this study is to investigate the pharmacokinetics and tolerance of DAS injection in healthy Chinese volunteers.

Methods:

This was a single-center, randomized, single-dose, three-way crossover design study. Nine eligible subjects were randomly divided into 3 groups, and each group sequentially received 80, 160, or 320 mg of DAS infusion according to a three-way Latin square design. Plasma and urine samples were collected and determined using an LC-MS/MS method. Safety and tolerability were determined via clinical evaluation and adverse event monitoring.

Results:

For the 80, 160, and 320 mg dose groups, the mean C_max were 4.82, 12.85, and 26.90 mg/L, respectively, and the mean AUC_0–12 were 6.18, 16.95, and 40.65 mg·L⁻¹·h, respectively. DAS was rapidly cleared, with a mean T_max of 0.94–1.0 h and a t_1/2 of approximately 1.51–1.89 h. Approximately 10.1%–15.5% of the intravenous DAS dose was excreted unchanged in urine within 24 h in the 3 groups, and more than 90% of unchanged DAS was excreted between 0 and 4 h. The pharmacokinetic profile was similar between male and female subjects. No serious or unexpected adverse events were found during the study, but one mild adverse event (stomachache) was reported.

Conclusion:

This study shows that DAS has nonlinear pharmacokinetic characteristics. To guarantee the effective concentration, mul¬tiple small doses are recommended in clinical regimens.     

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A,for the treatment of Alzheimer's disease

Aim:

Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects.

Methods:

This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including C_max, AUC_{0–72 h} and AUC_0–∞ were calculated. Tolerance assessments were conducted throughout the study.

Results:

ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean t_max of huperzine A was 0.76–0.82 h; the AUC_{0–72 h} and C_max of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed.

Conclusion:

ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.     

Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

AIM

To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y₁₂ receptor antagonist, in healthy volunteers.

METHODS

This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day⁻¹, or placebo for 14 days.

RESULTS

Ticagrelor was absorbed with median t_max 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean C_max and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified.

CONCLUSIONS

Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with C_max and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day⁻¹ was well tolerated.     

Safety,pharmacokinetics and pharmacodynamics of single/multiple doses of the oral,direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects

AIMS

To investigate the safety, pharmacokinetics and pharmacodynamics of rivaroxaban, an oral, direct Factor Xa (FXa) inhibitor, in healthy, male Chinese subjects.

METHODS

Two randomized, single-blind, placebo-controlled, dose-escalation studies were conducted in healthy Chinese men aged 18–45 years. In the single-dose study, subjects received single, oral doses of rivaroxaban 2.5, 5, 10, 20 and 40 mg. In the multiple-dose study, oral rivaroxaban was administered in doses of 5, 10, 20 and 30 mg twice daily for 6 days.

RESULTS

Rivaroxaban, in single and multiple doses up to 60 mg, was well tolerated. Rapid absorption was observed in both studies (time to C_max 1.25–2.5 h). In the multiple-dose study, rivaroxaban exposure increased dose-proportionally after the first dose and at steady state (for the 5–20-mg doses). The half-life of rivaroxaban was up to 7.9 h in the single-dose study. Maximal inhibition of FXa activity was achieved within 1–3 h of dosing in the single-dose study [at 20 mg FXa inhibition as a median percentage change from baseline, 45.92; 95% confidence interval (CI) 44.64, 50.70] and 2–3 h after administration at steady state in the multiple-dose study (at 20 mg median FXa inhibition as a median percentage change from baseline, 60.25; 95% CI 56.16, 63.05), in line with maximum rivaroxaban plasma concentrations.

CONCLUSIONS

Rivaroxaban demonstrated predictable pharmacokinetics and pharmacodynamics in healthy Chinese subjects, in line with findings observed previously in White subjects. This suggests that fixed doses of rivaroxaban may be administered to all patients, regardless of their ethnic origin.     

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects

Aims

The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics.

Methods

Healthy subjects, 18–55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1–2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days.

Results

The coadministration of CQ + TQ had no effect on TQ AUC_0–t, AUC_0–∞, T_max or t_1/2. The 90% confidence intervals of CQ + TQ vs. TQ for AUC_0–t, AUC_0–∞ and t_1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ C_max and AUC_0–24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated.

Conclusions

No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects.     

Pharmacokinetic–pharmacodynamic studies of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor MK-0916 in healthy subjects

Aims

To characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916.

Methods

Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4–100 mg MK-0916 (n = 16). In the second study, subjects received 0.2–225 mg MK-0916 followed by daily doses of 0.2–100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [¹³C₄]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [¹³C₄]cortisone.

Results

Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1–1.8 h). Exposure (measured as the area under the concentration–time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11β-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple E_max model with an IC₅₀ of 70.4 nm. Exposure to MK-0916 was generally well tolerated.

Conclusions

These findings indicate that 11β-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated.     

A contrast in safety,pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat

AIM

To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the γ-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women.

METHODS

All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-β (Aβ)_1–40 concentratios and exploration of Notch biomarkers.

RESULTS

Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median t_max between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,∞) values than those aged less than 75 years. An exploratory analysis of Aβ_1–40 serum concentrations showed a pattern of decreasing concentrations over the first 4–6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly.

CONCLUSIONS

The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer''s disease.     

Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants

AIMS

This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel.

METHODS

Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug''s active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)].

RESULTS

Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001).

CONCLUSIONS

Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.     

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

Aims

The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives.

Methods

An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban.

Results

During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (E_max) for INR after co-administration was 2.79–4.15 (mean PT E_max 41.0–62.7 s), compared with 1.41–1.74 (mean PT E_max 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug.

Conclusions

The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR.     

Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects

AIM

The aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects.

METHOD

This was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 μg for 7 days, then 800 μg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 μg infusion) in the other. FF PK and serum cortisol (inhaled 200 μg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed.

RESULTS

Ethnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%–55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 μg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1–30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated.

CONCLUSION

Modestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required.     

Pharmacokinetic evaluation of novel oral fluorouracil antitumor drug S-1 in Chinese cancer patients

Aim:

S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1.

Methods:

A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m², po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including C_max, T_max, t_1/2, AUC_0–t, and AUC_0–∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and C_max of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews.

Results:

The mean values of C_max, AUC_0–t, and AUC_0–∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of C_max, AUC_0–t, and AUC_0–∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found.

Conclusion:

The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m²) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.     

Apixaban,an oral,direct factor Xa inhibitor: single dose safety,pharmacokinetics, pharmacodynamics and food effect in healthy subjects

Aims

To evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics.

Methods

A double-blind, placebo-controlled, single ascending-dose, first-in-human study assessed apixaban safety, pharmacokinetics and pharmacodynamics in healthy subjects randomized to oral apixaban (n = 43; 0.5–2.5 mg as solution or 5–50 mg as tablets) or placebo (n = 14) under fasted conditions. An open label, randomized, two treatment crossover study investigated apixaban pharmacokinetics/pharmacodynamics in healthy subjects (n = 21) administered apixaban 10 mg in fasted and fed states. Both studies measured apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) or a modified PT (mPT).

Results

In the single ascending-dose study increases in apixaban exposure appeared dose-proportional. Median t_max occurred 1.5–3.3 h following oral administration. Mean terminal half-life ranged between 3.6 and 6.8 h following administration of solution doses ≤2.5 mg and between 11.1 and 26.8 h for tablet doses ≥5 mg. Concentration-related changes in pharmacodynamic assessments were observed. After a 50 mg dose, peak aPTT, INR and mPT increased by 1.2-, 1.6- and 2.9-fold, respectively, from baseline. In the food effect study: 90% confidence intervals of geometric mean ratios of apixaban C_max and AUC in a fed vs. fasted state were within the predefined no effect (80–125%) range. Apixaban half-life was approximately 11.5 h. The effect of apixaban on INR, PT and aPTT was comparable following fed and fasted administration.

Conclusions

Single doses of apixaban were well tolerated with a predictable pharmacokinetic/pharmacodynamic profile and a half-life of approximately 12 h. Apixaban can be administered with or without food.     

Safety,pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban,a factor Xa inhibitor,in healthy subjects

Aim

Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban.

Method

This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT).

Results

Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile.

Conclusion

Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.     

Ibudilast in healthy volunteers: safety,tolerability and pharmacokinetics with single and multiple doses

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibudilast is an oral drug approved in Asia for asthma.
• Tolerability of 10-mg regimens has been described previously.
• Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers.

WHAT THIS STUDY ADDS

• Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers.
• Higher-dose regimens are relevant for testing in new neurological indications.
• LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast).

AIMS

To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen.

METHODS

Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite.

RESULTS

Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median T_max was 4–6 h. Mean (SD) steady-state plasma C_max and AUC_0–24 were 60 (25) ng ml⁻¹ and 1004 (303) ng h ml⁻¹, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent.

CONCLUSIONS

Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day⁻¹) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.     

Pharmacodynamics,pharmacokinetics and safety of GSK2190915, a novel oral anti‐inflammatory 5‐lipoxygenase‐activating protein inhibitor

Aim

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5‐lipoxygenase‐activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations.

Method

Western European subjects received single (50–1000 mg) or multiple (10–450 mg) oral doses of GSK2190915 or placebo in a dose‐escalating manner. Japanese subjects received three of four GSK2190915 doses (10–200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B₄ and leukotriene E₄, respectively, as pharmacodynamic markers of drug activity.

Results

There was no clear difference in adverse events between placebo and active drug‐treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose‐related manner and mean half‐life values ranged from 16–34 h. Dose‐dependent inhibition of blood leukotriene B₄ production was observed and near complete inhibition of urinary leukotriene E₄ excretion was shown at all doses except the lowest dose. The EC₅₀ values for inhibition of LTB₄ were 85 nm and 89 nm in the Western European and Japanese studies, respectively.

Conclusion

GSK2190915 is well‐tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E₄ at 24 h post‐dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB₄.     

Grapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects

Aim

This study examined the effects of grapefruit juice on the new P2Y₁₂ inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.

Methods

In a randomized crossover study, 10 healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg dose of ticagrelor.

Results

Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (C_max) to 165% (95% confidence interval 147, 184%) and area under the concentration–time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The C_max and AUC(0,34 h) (P < 0.05) but not the AUC(0,∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity.

Conclusions

Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice–ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.     

Double-blind,randomized, placebo-controlled study of safety,tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men

Aims

Two randomized, double-blind, placebo-controlled studies were performed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational metastin analogue, TAK-683, in healthy men.

Methods

We first investigated a single subcutaneous (s.c.) dose of TAK-683 (0.01–2.0 mg) in 60 subjects (TAK-683, n = 42; placebo, n = 18). We then assessed a single s.c. bolus of 0.03–1.0 mg TAK-683 on day 1, followed by a 0.01–2.0 mg day⁻¹ continuous infusion on days 2–13, to simulate a depot formulation, in 30 subjects (TAK-683, n = 25; placebo, n = 5) for 14 days.

Results

TAK-683 was well tolerated up to a dose of 2.0 mg day⁻¹ by continuous s.c. infusion for 14 days. Adverse events were similar between TAK-683 and placebo subjects at all dose levels. TAK-683 plasma concentrations generally increased in proportion to dose with single and continuous dosing, with steady-state concentrations achieved by day 2 of continuous dosing. TAK-683 at 2.0 mg day⁻¹ suppressed testosterone below castration level (<50 ng dl⁻¹) in four of five subjects by day 7 of continuous dosing. Luteinizing hormone and follicle stimulating hormone concentrations were suppressed with TAK-683 continuous dosing compared with placebo by up to 70 and 43%, respectively, but this was not consistently dose-dependent.

Conclusions

In healthy men, s.c. administration of TAK-683 was well tolerated at all dose levels. The PK profile of TAK-683 was favourable, and TAK-683 suppressed testosterone profoundly during continuous dosing. Further investigation of metastin analogues is warranted for the treatment of castration-resistant prostate cancer.