Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein

AIMS

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP).

METHODS

The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20–45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60–5521 (n = 28) or were treated with a placebo (n = 10).

RESULTS

In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60–5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h.

CONCLUSIONS

BAY 60–5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated.     

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 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.     

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.     

Single-dose pharmacokinetics and pharmacodynamics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects

AIMS

Anacetrapib is an orally active and potent inhibitor of CETP in development for the treatment of dyslipidaemia. These studies endeavoured to establish the safety, tolerability, pharmacokinetics and pharmacodynamics of rising single doses of anacetrapib, administered in fasted or fed conditions, and to preliminarily assess the effect of food, age, gender and obesity on the single-dose pharmacokinetics and pharmacodynamics of anacetrapib.

METHODS

Safety, tolerability, anacetrapib concentrations and CETP activity were evaluated.

RESULTS

Anacetrapib was rapidly absorbed, with peak concentrations occurring at ∼4 h post-dose and an apparent terminal half-life ranging from ∼9 to 62 h in the fasted state and from ∼42 to ∼83 h in the fed state. Plasma AUC and C_max appeared to increase in a less than approximately dose-dependent manner in the fasted state, with an apparent plateau in absorption at higher doses. Single doses of anacetrapib markedly and dose-dependently inhibited serum CETP activity with peak effects of ∼90% inhibition at t_max and ∼58% inhibition at 24 h post-dose. An E_max model best described the plasma anacetrapib concentration vs CETP activity relationship with an EC₅₀ of ∼22 nm. Food increased exposure to anacetrapib; up to ∼two–three-fold with a low-fat meal and by up to ∼six–eight fold with a high-fat meal. Anacetrapib pharmacokinetics and pharmacodynamics were similar in elderly vs young adults, women vs men, and obese vs non-obese young adults. Anacetrapib was well tolerated and was not associated with any meaningful increase in blood pressure.

CONCLUSIONS

Whereas food increased exposure to anacetrapib significantly, age, gender and obese status did not meaningfully influence anacetrapib pharmacokinetics and pharmacodynamics.     

Pharmacokinetics and pharmacodynamics of ponesimod,a selective S1P1 receptor modulator,in the first-in-human study

Aims

This study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine-1-phosphate (S1P₁) receptor modulator in development for the treatment of auto-immune diseases.

Methods

This was a double-blind, placebo-controlled, ascending, single-dose study. Healthy male subjects received doses of 1–75 mg or placebo control.

Results

Ponesimod was well tolerated. Starting with a dose of 8 mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximal concentration ranged from 2.0 to 4.0 h, and ponesimod was eliminated with a mean half-life varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of ≥8 mg reduced total lymphocyte count in a dose-dependent manner. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts.

Conclusions

Single doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single-dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once-a-day dosing.     

The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review

Aim

The objective of this systematic review was to characterize the pharmacokinetics and pharmacodynamics of denosumab (XGEVA®), a fully human IgG2 monoclonal antibody which binds to receptor activator of nuclear factor kappa-B ligand (RANKL), for the treatment of skeletal-related events (SREs) in patients with advanced cancer and bone metastases.

Methods

A total of 708 patients (116 healthy patients and 592 patients with solid tumours or multiple myeloma and bone metastases) included in seven clinical studies were evaluated for denosumab pharmacokinetics. Denosumab was administered as a single subcutaneous (s.c.) dose or multiple s.c. doses, ranging from 0.1 to 3.0 mg kg⁻¹ or 30 mg to 180 mg fixed dosing, every 1 or 3 months for up to 45 months.

Results

Consistent with the results in healthy adults, single s.c. doses of denosumab demonstrated dose-dependent, non-linear pharmacokinetics in advanced cancer patients with bone metastases across a wide dose range (0.1–3.0 mg kg⁻¹). Reductions in levels of the bone turnover marker, uNTx/Cr, were observed within 1 day. The duration of reductions generally increased with dose and dosing frequency. In patients with solid tumours and bone metastases, pharmacokinetics and pharmacodynamic comparisons across tumour types and concomitant cancer therapies (chemotherapies and/or hormone therapies) suggest that neither tumour type nor type of concomitant therapy markedly affects denosumab pharmacokinetics or pharmacodynamics.

Conclusions

Denosumab displayed non-linear pharmacokinetics at doses below 60 mg but at higher doses, denosumab exposure increased approximately dose-proportionally in advanced cancer patients with bone metastases. Following a 120 mg, every 4 weeks dosing schedule, similar denosumab pharmacokinetics and pharmacodynamics were observed across tumour types and were independent of concomitant cancer therapies.     

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.     

Effect of repeated doses of netazepide,a gastrin receptor antagonist,omeprazole and placebo on 24 h gastric acidity and gastrin in healthy subjects

Aim

To administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics and effect on 24 h gastric pH and plasma gastrin.

Method

We did two randomized, double-blind, parallel group studies. The first compared netazepide 25 and 100 mg 12 hourly, omeprazole 20 mg once daily and placebo for 7 days. On day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25 mg and placebo once daily for 14 days. We measured pH on days 1, 7 and 14 and assayed plasma gastrin on days 1 and 14. We compared treatments by time gastric pH ≥ 4 during 0–4, 4–9, 9–13 and 13–24 h after the morning dose, and by plasma gastrin. P < 0.05 was significant.

Results

Netazepide was well tolerated. On day 7 of the first study, netazepide increased pH significantly only during 9–13 h after the 100 mg dose, whereas omeprazole raised pH significantly during all periods. Both netazepide and omeprazole increased plasma gastrin significantly. Netazepide had linear pharmacokinetics. In the second study, netazepide caused dose-dependent, sustained increases in pH on day 1, but as in the first study, netazepide had little effect on pH on days 7 and 14. Again, netazepide increased plasma gastrin significantly.

Conclusion

Although repeated doses of netazepide led to tolerance to its effect on pH, the accompanying increase in plasma gastrin is consistent with continued inhibition of acid secretion, via gastrin receptor antagonism and gene up-regulation.     

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.     

Absence of Pharmacokinetic and Pharmacodynamic Interactions between Almorexant and Warfarin in Healthy Subjects

Background and Objective

Almorexant is the first representative of the new class of orexin receptor antagonists, which could become a new treatment option for insomnia. The present study investigated the potential interaction between almorexant and warfarin.

Methods

In this open-label, two-way crossover, drug–drug interaction study, healthy male subjects received, in a randomized fashion, almorexant 200 mg once daily for 10 days and a single dose of 25 mg warfarin co-administered on day 5 (treatment A) and a single dose of 25 mg warfarin on day 1 (treatment B). Serial blood samples for warfarin pharmacokinetics and pharmacodynamics were drawn during both treatments.

Results

Of the 14 enrolled subjects, one withdrew due to an adverse event and 13 completed the study. Almorexant had no effect on the pharmacokinetics of warfarin. The geometric mean ratios (90 % confidence interval) for the area under the plasma concentration–time curve to infinity (AUC_0–∞) of S- and R-warfarin were 0.99 (0.89, 1.09) and 1.05 (0.95, 1.16), respectively, and for the maximum plasma concentration (C_max) were 0.99 (0.86, 1.14) and 1.00 (0.88, 1.13), respectively. The main pharmacodynamic variable was the AUC for the international normalized ratio (AUC_INR). Almorexant had no effect on this variable as demonstrated by a geometric mean ratio of 0.99 (0.82, 1.19). Secondary pharmacodynamic variables including maximum effect (E_max), the time to the maximum INR, and factor VII plasma concentrations were also not affected by almorexant.

Conclusion

No dose adjustment of warfarin is necessary when concomitantly administered with almorexant.     

Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban,an oral,direct Factor Xa inhibitor

Aim

This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor.

Method

This single centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child–Pugh classification, and gender-matched healthy subjects (n = 16).

Results

Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration–time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold [90% confidence interval (CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect–time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment.

Conclusion

Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects.     

Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic,in a first-in-human study

Aims

The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM).

Methods

T2DM subjects (glycosylated haemoglobin: 7.0–10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5–200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride – an early marker of drug activity.

Results

No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5–7.7 h and 66.5– 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups.

Conclusions

Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.     

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.     

Effect of extremes of body weight on the pharmacokinetics,pharmacodynamics, safety and tolerability of apixaban in healthy subjects

Aim

Apixaban is an oral, direct, factor-Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This open label, parallel group study investigated effects of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability.

Method

Fifty-four healthy subjects were enrolled [18 each into low (≤50 kg), reference (65–85 kg) and high (≥120 kg) body weight groups]. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti-factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored.

Results

Compared with the reference body weight group, low body weight had approximately 27% [90% confidence interval (CI): 8–51%] and 20% (90% CI: 11–42%) higher apixaban maximum observed plasma concentration (C_max) and area under the concentration–time curve extrapolated to infinity (AUC_(0,∞)), respectively, and high body weight had approximately 31% (90% CI: 18–41%) and 23% (90% CI: 9–35%) lower apixaban C_max and AUC_(0,∞), respectively. Apixaban renal clearance was similar across the weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study.

Conclusion

The modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone. However, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure.     

Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment

Aims

To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT®) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function.

Methods

Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein).

Results

Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total mifamurtide AUC_inf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6–132%) and 119% (90% confidence interval, 94.1–151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered mifamurtide (4 mg).

Conclusions

These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations.     

Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects

Aim:

To characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and tolerability of different dose regimens of prasugrel in healthy Chinese subjects.

Methods:

This was a single-centered, open-label, parallel-design study. Subjects received a single loading dose (LD) of prasugrel followed by once-daily maintenance dose (MD) for 10 d. They were enrolled into 3 groups: 60 mg LD/10 mg MD; 30 mg LD/7.5 mg MD; 30 mg LD/5 mg MD. Blood samples were collected after the first and last dose. The serum concentration of the active metabolite of prasugrel was determined using a LC/MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y₁₂ assay.

Results:

Thirty-six healthy native Chinese subjects (19 males) aged 18–45 were enrolled; mean age and body weight were similar across the treatment groups (n=12 for each). The metabolite AUC_0–4 and C_max increased dose-proportionally across the dose range of 5 mg to 60 mg. The median T_max was 0.5 h in all groups. The PD parameters, indicated by the inhibition of ADP-induced platelet aggregation, were met more rapidly in the 60 mg group than the 30 mg group after the LD (94%–98%). This high degree of inhibition of platelet aggregation was maintained following the 10 mg MD (87%–90%) and was lower in the 7.5 mg and 5 mg MD groups (79%–83% and 64%–67%, respectively). Prasugrel was well tolerated in healthy Chinese subjects for single doses up to 60 mg and a MD of 10 mg for 10 d.

Conclusion:

The PKs and PDs of the active metabolite of prasugrel were similar to those in Chinese subjects reported by a previous bridging study, which demonstrated that the exposure to the active metabolite in Chinese subjects was higher than in Caucasians.     

Pharmacokinetics,Safety, and Tolerability of GLPG0259, a Mitogen-Activated Protein Kinase-Activated Protein Kinase 5 (MAPKAPK5) Inhibitor,Given as Single and Multiple Doses to Healthy Male Subjects

Background and Objectives

GLPG0259 is a small-molecule inhibitor of mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5), a kinase enzyme that plays a role in important inflammatory pathways. The main objectives of the phase I clinical studies in early development were to characterize the pharmacokinetics, tolerability, and safety of GLPG0259 in healthy subjects, including the development of a solid dosage form (free-base pellets and fumarate salt capsules) and the potential for interaction of GLPG0259 with methotrexate.

Subjects and Methods

Four phase I studies were initiated. Study 1 was a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses (1.5–150 mg) and multiple oral doses (20 and 50 mg once daily) of GLPG0259 in healthy male subjects (n = 34). Study 2 was a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral multiple ascending doses of GLPG0259 (25–75 mg once daily) given for 14 days to healthy male subjects, and to get preliminary information on the potential pharmacokinetic interaction between GLPG0259 and methotrexate (n = 24). Studies 3 and 4 were open-label, randomized, crossover studies to compare the oral bioavailability of two solid dosage forms of GLPG0259 (a capsule) relative to an oral solution after a 100 mg or 50 mg single dose and to evaluate the effect of food on these formulations (n = 12 for each study).

Main Outcome Measures

The non-compartmental pharmacokinetic parameters for plasma concentrations of GLPG0259 were determined, and a population pharmacokinetic model of GLPG0259 was developed to support the planning of the number and timing of the sparse samples to be taken per patient in the phase II study. Safety and tolerability data are also summarized.

Results

The absorption of GLPG0259 was slow, with a decrease in the absorption rate with increasing dose, and there was decreased elimination, with an apparent terminal elimination half-life of 26.0 hours. On the basis of statistical analysis of variance, the exposure to GLPG0259 increased in proportion to the dose over a 30–150 mg single-dose range and a 25–75 mg repeated-dose range. Between- and within-subject variability in GLPG0259 pharmacokinetics was low/moderate (coefficient of variation [CV] 16–30%). After once-daily repeated dosing, steady-state plasma concentrations were reached at between 5 and 8 dosing days, which is consistent with the long apparent elimination half-life of GLPG0259. Food increased the bioavailability of GLPG0259 given in a solid dosage form. Co-administration of GLPG0259 with a single dose of methotrexate 7.5 mg did not result in any change in the pharmacokinetic profiles of either GLPG0259 or methotrexate.

Conclusion

In summary, the investigation of safety/tolerability and pharmacokinetics in the early development phase showed that single and repeated doses of GLPG0259 were safe and well tolerated. The most common adverse event reported was mild gastrointestinal discomfort. The pharmacokinetics characterized in healthy male subjects showed no major obstacles and supports a once-daily oral regimen in patients.     

Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate renal impairment

Aims

To evaluate the pharmacokinetics and pharmacodynamics following a single dose of liposomal mifamurtide (L-MTP-PE, MEPACT®) in adult subjects with mild (calculated creatinine clearance [CL_cr] of 50–80 ml min⁻¹) or moderate (CL_cr 30–50 ml min⁻¹) renal impairment in comparison with age-, weight- and gender-matched healthy subjects with normal renal function (CL_cr >80 ml min⁻¹).

Methods

Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for analysis of plasma pharmacokinetics of total and non-liposome-associated (free) mifamurtide and assessment of pharmacodynamics (changes in serum interleukin-6 [IL-6], tumour necrosis factor-α [TNF-α], C-reactive protein [CRP]).

Results

Thirty-three subjects were enrolled: nine with mild renal impairment, eight with moderate renal impairment and 16 healthy subjects. Geometric mean (%CV) AUC_inf for total mifamurtide was 89.5 (58.1), 94.8 (27.8), 85.1 (29.0), 95.4 (18.1) nm h in the mild renal impairment, mild-matched healthy subject, moderate renal impairment and moderate-matched healthy subject groups, respectively. Mifamurtide clearance was not correlated with CL_cr, estimated glomerular filtration rate or iohexol clearance (all r² < 0.01). AUC_inf of free mifamurtide was similar across the renal function groups. There were no readily apparent differences in serum pharmacodynamic effect parameters (baseline-adjusted AUEC_last for IL-6 and TNF-α and E_max for CRP) between the renal function groups. No subjects reported grade ≥3 or serious adverse events.

Conclusions

Mild or moderate renal impairment does not alter the clinical pharmacokinetics or pharmacodynamics of mifamurtide. No dose modifications appear necessary for these patients based on clinical pharmacologic considerations.