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.     

Evidence for oxazepam as an in vivo probe of UGT2B15: oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion

AIMS

Although in vitro studies indicate that oxazepam is an isoform-selective substrate probe for UDP-glucuronosyltransferase 2B15, the utility of this drug as an in vivo probe is uncertain. The main aim of this study was to determine whether common missense polymorphisms in the UGT2B15 gene (D85Y and K523T) are associated with altered oxazepam pharmacokinetics and pharmacodynamics. We also determined the possible influence of a common deletion polymorphism in the gene encoding UGT2B17, which shows substantial substrate specificity overlap with UGT2B15.

METHODS

Thirty healthy male subjects were administered 15 mg of oxazepam by mouth followed by plasma oxazepam concentration monitoring for 36 h, and pharmacodynamic testing for 8 h. Genotypes were determined by genomic polymerase chain reaction and commercial 5′-nuclease assays.

RESULTS

Allele frequencies for D85Y, K523T, UGT2B17del were 47%, 23% and 19%, respectively. Median oxazepam apparent oral clearance was significantly lower in 85YY subjects (1.62 ml min⁻¹ kg⁻¹) compared with 85DD subjects (3.35 ml min⁻¹ kg⁻¹; P= 0.003, Student–Newman–Keuls test), whereas 85DY subjects were intermediate (2.34 ml min⁻¹ kg⁻¹; P= 0.018 vs. 85DD, P= 0.034 vs. 85YY). Regression analysis indicated that UGT2B15 D85Y genotype accounted for 34% of interindividual variability. However, neither UGT2B15 K523T nor UGT2B17del was associated with altered oxazepam disposition. Furthermore, no differences in pharmacodynamic measures, including quantitative electroencephalography, digit-symbol substitution test, self- or observer-rated visual analogue scales, could be demonstrated for any of the polymorphisms evaluated.

CONCLUSIONS

These results identify UGT2B15 D85Y as a major determinant of oxazepam clearance, and indicate that oxazepam may be useful as an in vivo probe for glucuronidation by UGT2B15.     

The concentration of oxazepam and oxazepam glucuronide in oral fluid, blood and serum after controlled administration of 15 and 30 mg oxazepam

AIMS

To measure and compare the concentration–time profiles of oxazepam and oxazepam glucuronide in blood, serum and oral fluid within the scope of roadside testing.

METHODS

Biological samples were collected from eight male subjects after ingestion of 15 or 30 mg oxazepam on separate dosing occasions with an interval of 7 days. The concentration–time profiles of oxazepam and oxazepam glucuronide were fitted by using a one-compartment model.

RESULTS

For oxazepam and oxazepam glucuronide, the mean oral fluid/blood ratios were 0.05 (range 0.04–0.07) and 0.004 (range 0.002–0.006), respectively. The concentration–time profiles in oral fluid paralleled those in blood.

CONCLUSION

After oral administration of therapeutic doses of oxazepam, concentrations in oral fluid are very much lower than those in blood, and those of oxazepam glucuronide are much lower than those of the parent compound. Nevertheless, assay of oral fluid for oxazepam can be used to detect recent ingestion of the drug in drivers suspected of impaired driving performance.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Concentration–time profiles of drugs in oral fluid generally run parallel to those in blood.
• In general, oral fluid contains more parent drug than metabolites.
• For some benzodiazepines it has been shown that concentrations are lower in oral fluid than in blood.

WHAT THIS STUDY ADDS

• The concentration–time profile of oxazepam in oral fluid after a single dose of oxazepam runs parallel to blood and is dose dependent.
• Concentration ratios (oral fluid/blood and oral fluid/serum) of oxazepam and oxazepam glucuronide after controlled intake of a single dose of oxazepam are presented.

     

Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?

AIM

The aim of this small patient study was to investigate tamsulosin concentrations in prostate and plasma samples in order to identify potential differences in the pharmacokinetics (PK) in plasma and prostate contributing to its pharmacodynamic activity profile in patients.

METHODS

Forty-one patients with benign prostatic hyperplasia (BPH) scheduled for open prostatectomy were given tamsulosin 0.4 mg for 6–21 days in order to reach steady-state PK. Patients were randomized over four groups to allow collection of plasma and tissue samples at different time points after last dose administration. Samples were collected during surgery and assayed for tamsulosin HCl. The free fraction (f_u) of tamsulosin was determined by ultracentrifugation of plasma and prostate tissue spiked with ¹⁴C-tamsulosin.

RESULTS

C_max in plasma at 4.4 h for total tamsulosin was 15.2 ng ml⁻¹ and AUC(0,24 h) was 282 ng ml⁻¹ h, while for prostate C_max at 11.4 h post-dose was 5.4 ng ml⁻¹ and AUC(0,24 h) was 120 ng ml⁻¹ h. AUC(0,24 h) for total tamsulosin in prostate was 43% of the plasma AUC(0,24 h). f_u was 0.4 % for plasma and 59.1% for prostate. Therefore calculated on unbound tamsulosin, a ratio of 63 resulted for prostate vs. plasma C_max concentrations.

CONCLUSIONS

These data indicate that in patients with confirmed BPH the amount of tamsulosin freely available in the target tissue (prostate) is much higher than in plasma.     

The pharmacokinetic profile of sitaxsentan, a selective endothelin receptor antagonist, in varying degrees of renal impairment

What is already known about this subject

• The initial indication for endothelin (ET) receptor antagonism as a treatment strategy, primary pulmonary hypertension, is now expanding to include scleroderma, which can cause both pulmonary and renal disease.
• It is important to understand the effects of impaired renal function on the pharmacokinetics of these drugs to allow appropriate dosing in individuals with impaired renal function.

What this study adds

• Sitaxsentan, an oral selective endothelin A receptor antagonist, is licensed for the treatment of pulmonary hypertension, and studies of this drug in CKD are planned.
• The pharmacokinetic profile of sitaxsentan is unchanged in subjects with varying degrees of renal impairment.
• The results of this study will allow confident dosing of sitaxsentan in individuals with renal impairment, and inform future studies.

Aim

To investigate the pharmacokinetic profile of a single 100-mg oral dose of sitaxsentan, a selective endothelin type A receptor antagonist, in subjects with normal and impaired renal function.

Methods

This was an open label, single oral dose study in subjects with normal [creatinine clearance (CrCL) ≥ 80 ml min⁻¹] and impaired renal function (mild renal impairment CrCL 51–80 ml min⁻¹, moderate impairment CrCL 31–50 ml min⁻¹, severe impairment CrCL ≤ 30 ml min⁻¹). All subjects received a dose of 100 mg sitaxsentan.

Results

Twenty-four subjects were enrolled, six in each of the normal and three renal impairment groups. The mean plasma sitaxsentan concentrations were comparable across the groups, as were the mean values for C_max (10.3–13.9 µg ml⁻¹), AUC_∞ (18.7–22.5 h µg⁻¹ ml⁻¹), oral clearance (CL/F, 82.3–94.9 ml min⁻¹), volume of distribution (Vz/F, 64.8–69.6 l) and elimination half-life (t_1/2, 8.6–9.6 h). There was substantial overlap among the four groups in the individual subject values for CL/F and Vz/F and no relationship between either of these parameters and CrCL.

Conclusion

After a single 100-mg oral dose of sitaxsentan there were no differences in its pharmacokinetics among subjects with normal or impaired renal function.     

Population pharmacokinetics and optimal design of paediatric studies for famciclovir

AIMS

To develop a population pharmacokinetic model for penciclovir (famciclovir is a prodrug of penciclovir) in adults and children and suggest an appropriate dose for children. Furthermore, to develop a limited sampling design based on sampling windows for three different paediatric age groups (1–2, 2–5 and 5–12 years) using an adequate number of subjects for future pharmacokinetic studies.

METHODS

Penciclovir plasma data from six different adult and paediatric studies were supplied by Novartis. Population pharmacokinetic modelling was undertaken in NONMEM version VI. Simulations in MATLAB were used to select an oral paediatric dose that gives similar exposure to 500 mg in adults. Optimal sampling times and sampling windows were obtained in MATLAB and simulations in NONMEM were used to select adequate sample sizes for three paediatric age groups.

RESULTS

A two-compartment, first-order absorption model with an absorption lag time, allometric weight models on V₁, V₂ and Q, and an allometric weight model, age and creatinine clearance as covariates on CL adequately describe the pharmacokinetics of penciclovir in adults and children. Estimated CL (l h⁻¹ 70 kg⁻¹) and V_ss (l.70 kg⁻¹) were 31.2 and 83.1, respectively. An oral dose of 10 mg kg⁻¹ body weight in children was predicted to give similar exposure as 500 mg in adults. A single sampling windows design (0.25–0.4, 0.5–1, 1.25–1.75, 2.75–3.5 and 7.25–8 h) for five samples per subject and 10 subjects in each of the paediatric age groups is recommended for future studies.

CONCLUSIONS

A population pharmacokinetic model of penciclovir in adults and children has been developed. A prospective study design, including dose adjustment, cohort size and blood sampling design has been recommended.     

Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor

AIM

This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10 mg single dose), an oral, direct Factor Xa inhibitor.

METHODS

Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80 ml min⁻¹), mild (50–79 ml min⁻¹), moderate (30–49 ml min⁻¹) and severe impairment (<30 ml min⁻¹).

RESULTS

Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration–time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively.

CONCLUSIONS

Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.     

Effect of renal impairment on the pharmacokinetics of PD 0200390, a novel ligand for the voltage-gated calcium channel alpha-2-delta subunit

AIMS

To investigate the pharmacokinetics and safety of PD 0200390 in healthy subjects and subjects with renal impairment (RI) and to examine the relationship between oral and renal PD 0200390 clearance and estimated creatinine clearance (CLcr).

METHODS

In this open-label study, 26 subjects were categorized into four groups based on renal function: no RI (CLcr >80 ml min⁻¹; n= 6); mild RI (CLcr 51 to ≤80 ml min⁻¹; n= 6); moderate RI (CLcr >30 to 50 ml min⁻¹; n= 6); and severe RI (CLcr ≤30 ml min⁻¹; n= 8). Subjects received a single, oral dose of PD 0200390 25 mg. Noncompartmental pharmacokinetic parameters were determined from plasma and urine concentration–time data.

RESULTS

PD 0200390 was rapidly absorbed; mean time to maximum plasma concentration was 1.66–3.24 h. Mean half-life in subjects with normal renal function was 5.36 h, and increased with worsening RI. Oral (CL/F) and renal (CL_R) clearance rates decreased with deteriorating renal function, whereas area under the concentration–time curve (AUC_0–∞) values increased by 56, 117 and 436% in subjects with mild, moderate and severe RI, respectively, indicating increased PD 0200390 exposure. Regression analysis demonstrated that CL/F and CL_R correlated with CLcr (r= 0.953 and 0.961, respectively). PD 0200390 was well tolerated in subjects with mild, moderate or no RI. The most common adverse events were somnolence, dizziness and headache; these occurred with greatest intensity in the severe RI group.

CONCLUSIONS

PD 0200390 pharmacokinetic parameters (CL/F, CL_R and AUC_0–∞) vary predictably with decreases in renal function; therefore dose adjustment may be required in individuals with RI.     

Pharmacokinetics of enteric-coated cysteamine bitartrate in healthy adults: a pilot study

AIMS

Cysteamine bitartrate (Cystagon®) is the approved treatment for cystinosis. Poor compliance and patient outcome may occur because the drug needs to be taken every 6 h and in some patients causes gastrointestinal symptoms due to hypergastrinaemia. A formulation of cysteamine requiring twice daily ingestion would improve the quality of life for these patients. This study compares the pharmacokinetics and gastrin production following cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated in normal healthy subjects.

METHODS

Enteric-coated cysteamine was prepared. Following single doses of cysteamine bitartrate non-enteric-coated 450 mg and cysteamine bitartrate enteric-coated 450 mg and 900 mg, serial plasma cysteamine and gastrin concentrations were measured. Two subjects also received cysteamine bitartrate non-enteric-coated 900 mg. Gastrointestinal (GI) symptoms were recorded.

RESULTS

Six healthy adults (mean age 20.7 years, range 18–24 years; mean weight 59.3 kg) received drug. All post-dose gastrin concentrations were within the normal range (<100 pg ml^–1). The t_max following cysteamine bitartrate non-enteric-coated (mean and SD is 75 ± 19 min) was shorter than cysteamine bitartrate enteric-coated (220 ± 74 min) (P = 0.001), but only the C_max and AUC estimates following 900 mg cysteamine bitartrate enteric-coated were significantly greater than any of the other preparations or doses (P < 0.05). One patient had GI symptoms following both 900 mg cysteamine bitartrate non-enteric-coated and cysteamine bitartrate enteric-coated.

CONCLUSION

Although patient numbers were low, single high doses of cysteamine bitartrate enteric-coated were better tolerated than similar doses of cysteamine bitartrate non-enteric-coated in the healthy subjects and all had normal gastrin concentrations. The delayed t_max following cysteamine bitartrate enteric-coated suggested that the cysteamine was released enterically.     

Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects

AIM

To assess the two-way pharmacokinetic interaction between voriconazole and Ortho-Novum® 1/35, an oral contraceptive containing norethindrone 1 mg and ethinyl oestradiol 35 μg.

METHODS

In this open-label, three-period, fixed-sequence study, 16 healthy females received voriconazole (400 mg q12 h, day 1; 200 mg q12 h, days 2–4) (period 1), oral contraceptive (q24 h, days 12–32) (period 2), and combination voriconazole (400 mg q12 h, day 57; 200 mg q12 h, days 58–60) and oral contraceptive (q24 h, days 40–60) (period 3).

RESULTS

Voriconazole geometric mean AUC_τ and C_max increased 46% (12 682–18 495 ng h ml⁻¹; 90% confidence interval [CI] 32, 61) and 14% (2485–2840 ng ml⁻¹; 90% CI 3, 27), respectively, when co-administered with oral contraceptive vs. voriconazole alone. Ethinyl oestradiol geometric mean AUC_τ and C_max increased 61% (1031–1657 ng h ml⁻¹; 90% CI 50, 72) and 36% (119–161 ng ml⁻¹; 90% CI 28, 45), respectively, and norethindrone geometric mean AUC_τ and C_max increased 53% (116–177 ng h ml⁻¹; 90% CI 44, 64) and 15% (18–20 ng ml⁻¹; 90% CI 3, 28), respectively, during voriconazole co-administration vs. oral contraceptive alone. Neither ethinyl oestradiol nor norethindrone levels were reduced in subjects following voriconazole co-administration. Adverse events (AEs) were generally mild, occurring less in subjects receiving voriconazole alone (36 events) vs. oral contraceptive alone (88 events) or combination treatment (68 events); four subjects experienced a severe AE.

CONCLUSIONS

Co-administration of voriconazole and oral contraceptive increased systemic exposures of all analytes relative to respective monotherapy. Although generally safe and well tolerated, it is recommended that patients receiving co-administered voriconazole and oral contraceptive be monitored for development of AEs commonly associated with these medications.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Voriconazole, a broad-spectrum antifungal drug, is a substrate and inhibitor of CYP2C19 and CYP3A4 isozymes.
• Ethinyl oestradiol and norethindrone, components of the combination oral contraceptive drug Ortho-Novum® 1/35, also are substrates of cytochrome P450 CYP2C19 and CYP3A4 isozymes.
• Because co-administration of voriconazole and Ortho-Novum® 1/35 could potentially result in pharmacokinetic interactions that increase systemic exposure of one or both drugs to unsafe levels, clinical studies are needed to define better the two-way pharmacokinetic interaction between these drugs.

WHAT THIS STUDY ADDS

• Although co-administered voriconazole and oral contraceptive did result in increased systemic exposures of all three drugs relative to respective monotherapy, co-administered treatment was generally safe and well tolerated.
• It is recommended, however, that patients receiving co-administered voriconazole and oral contraceptives be monitored for the development of adverse events commonly associated with these medications.

     

Baseline albuminuria predicts the efficacy of blood pressure-lowering drugs in preventing cardiovascular events

AIMS

Albuminuria has been proven to be associated with cardiovascular (CV) events in specific patient populations, but also in the general population. This study aimed to investigate whether the efficacy of blood pressure-lowering agents in preventing CV events depends on baseline urinary albumin excretion (UAE) and, if so, whether this holds true for blood pressure-lowering agents in general, or is limited to agents that interfere in the renin–angiotensin system.

METHODS

Data were used from a community-based cohort study and pharmacy dispensing records. Included were subjects with hypertension (systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 mmHg), no cardiovascular disease history, and no previous use of blood pressure-lowering agents.

RESULTS

During study follow-up (7.1 ± 1.6 years), 122 CV events were observed in 1185 subjects included. Start of blood pressure-lowering agents vs. non-use was associated with a difference in absolute CV event risk of 0.7%, 6% and 12.6% for all subjects, those with UAE ≥ 15 mg day⁻¹ and ≥30 mg day⁻¹, respectively. Cox regression analysis showed that the relative risk for CV events after start of blood pressure-lowering agents was significantly dependent (P < 0.05) on baseline UAE; with hazard ratios of 0.87 [95% confidence interval (CI) 0.48, 1.60, P = NS], 0.58 (95% CI 0.36, 0.94, P < 0.05) and 0.37 (95% CI 0.20, 0.68, P < 0.05), for subjects with UAE < 15, ≥15 and ≥30 mg day⁻¹, respectively. Results adjusted for covariates were essentially similar. The use of angiotensin converting enzyme inhibitor/angiotensin-II receptor blocker (ACEi/ARB) treatment tended to be associated with a more favourable CV prognosis when compared with non-ACEi/ARB treatment (difference P = 0.06).

CONCLUSIONS

Our results suggest that the efficacy of blood pressure-lowering agents to prevent CV events is dependent on baseline albuminuria. The higher baseline albuminuria, the more absolute as well as relative risk reduction can be achieved. Our data suggest that this may especially be true for ACEi/ARBs. We caution that this is an observational study, and that these conclusions should therefore be regarded as hypothesis generating, rather than hypothesis testing.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Albuminuria has been proven to be associated with cardiovascular morbidity and mortality.
• Such an association has been found not only in subjects with diabetes and hypertension, but also in the general population.
• It could therefore be expected that especially subjects with higher albuminuria levels may benefit from blood pressure-lowering agents to improve their cardiovascular outcome.

WHAT THIS STUDY ADDS

• This study indicates that the efficacy of blood pressure-lowering agents to prevent cardiovascular events is dependent of the level of albuminuria before start of such treatment.
• The higher baseline albuminuria, the better the relative and absolute risk reduction for cardiovascular events with blood pressure-lowering drugs.
• The data also suggest a possible better cardiovascular protective effect of renin–angiotensin intervening agents compared with other blood pressure-lowering agents.

     

The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men

AIMS

Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects.

METHODS

Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day⁻¹ (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days.

RESULTS

Brivaracetam was rapidly absorbed (t_max∼2 h) and eliminated (t_1/2 7–8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5–8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-β-hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system-related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose-related sedation and decreased alertness that only persisted at 800 mg daily.

CONCLUSIONS

Brivaracetam was well tolerated by healthy male volunteers at doses of 200–800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetic profile, metabolism and proof of concept of a single oral dose of brivaracetam have been reported.
• Previous studies have shown that it was well absorbed, had linear kinetics and was well tolerated, and suggested effective doses of 10–80 mg in photoparoxysmal epilepsy.

WHAT THIS STUDY ADDS

• We now report the pharmacokinetics, pharmacodynamics and tolerability in healthy volunteers after multiple doses.

     

Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study

AIMS

To assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects.

METHODS

Forty-five healthy adult subjects (38 men and seven women) were randomly assigned to receive a single i.v. dose of placebo or sirukumab (0.3, 1, 3, 6 or 10 mg kg⁻¹ in a dose-escalating manner). All treated subjects were observed for 96 h post infusion and underwent 20-week follow-up evaluations. Serum samples were collected to measure sirukumab concentrations, pharmacodynamic biomarkers and antibodies to sirukumab. Non-compartmental analysis and population PK modelling were conducted to characterize the PK of sirukumab.

RESULTS

Adverse events were generally brief in duration, mild or moderate in intensity and non-dose-dependent. No serious adverse events were observed in the sirukumab-treated subjects. Both C_max and AUC(0,∞) increased in an approximately dose-proportional manner. Median terminal half-life ranged from 18.5 to 29.6 days. A two-compartment model adequately described the PK of sirukumab following i.v. administration. Population estimates for the clearance (CL), the central volume of distribution (V₁), the inter-compartmental clearance (Q) and the peripheral volume of distribution (V₂) were 0.364 l day⁻¹, 3.28 l, 0.588 l day⁻¹ and 4.97 l, respectively. Compared with placebo subjects, a sustained decrease from baseline in C-reactive protein was observed in all sirukumab-treated dose groups, although no clear dose–response relationship was observed. No subjects were positive for antibodies to sirukumab.

CONCLUSIONS

Sirukumab had a well-tolerated safety profile, desirable PK characteristics and a low incidence of immunogenicity following an i.v. infusion of 0.3 to 10 mg kg⁻¹ in healthy subjects.     

Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure

AIMS

The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil.

METHODS

Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V.

RESULTS

The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E_max model with E_max of −11.7 mmHg and EC₅₀ of 423 µg l⁻¹ was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h.

CONCLUSIONS

AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 µg l⁻¹, indicating that a loading dose of 200 µg kg⁻¹ and a maintenance dose of 400 µg kg⁻¹ h⁻¹ would be appropriate for the initial treatment of AHF.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Nicorandil injection is used for unstable angina and for acute heart failure in Japan.
• The pharmacokinetics of nicorandil following oral administration have been described in healthy subjects.

WHAT THIS STUDY ADDS

• This paper describes the differences in nicorandil pharmacokinetics between healthy subjects and acute heart failure patients.
• A population pharmacokinetic-pharmacodynamic model for nicorandil in acute heart failure patients is described using pulmonary artery wedge pressure as the biomarker.
• A rational guide for initial dosing of nicorandil to achieve a target effect on pulmonary artery wedge pressure was based on pharmacokinetic and pharmacodynamic principles.

     

Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420

AIMS

The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug''s pharmacokinetics and dose proportionality.

METHODS

This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n = 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C_max and AUC(0,∞).

RESULTS

PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C_max was reached at a median t_max of approximately 1 h post dose (range 0.32–2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t_1/2 ranging from 2.42–2.61 h (range 1.64–3.95 h) across all dose levels.

CONCLUSIONS

Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2–8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.     

No significant effect of SLCO1B1 polymorphism on the pharmacokinetics of rosiglitazone and pioglitazone

AIMS

To examine possible effects of polymorphism in the SLCO1B1 gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, on the pharmacokinetics of rosiglitazone and pioglitazone in a prospective genotype panel study.

METHODS

Sixteen healthy volunteers with the homozygous SLCO1B1 c.521TT genotype (controls), 12 with the heterozygous c.521TC genotype and four with the homozygous c.521CC genotype ingested a single 4-mg dose of rosiglitazone and a single 15-mg dose of pioglitazone in a cross-over study with a wash-out period of at least 1 week.

RESULTS

SLCO1B1 polymorphism had no statistically significant effect on any of the pharmacokinetic variables of rosiglitazone, pioglitazone or their metabolites. The mean ± SD area under the plasma rosiglitazone concentration–time curve from time 0 to infinity (AUC_0–∞) was 2024 ± 561 ng ml⁻¹ h in the c.521TT subjects, 1763 ± 288 ng ml⁻¹ h in the c.521TC subjects (geometric mean ratio c.521TC/c.521TT 0.89; 95% confidence interval 0.72, 1.11) and 1729 ± 346 ng ml⁻¹ h in the c.521CC subjects (c.521CC/c.521TT 0.87; 0.63, 1.20). The AUC_0–∞ of pioglitazone averaged 6244 ± 1909 ng ml⁻¹ h in the c.521TT subjects, 5123 ± 1165 ng ml⁻¹ h in the c.521TC subjects (c.521TC/c.521TT 0.83; 0.65, 1.06) and 4851 ± 1123 ng ml⁻¹ h in the c.521CC subjects (c.521CC/c.521TT 0.79; 0.55, 1.14). There was a significant correlation between the AUC_0–∞ of rosiglitazone and pioglitazone (r = 0.717, P < 0.001).

CONCLUSIONS

The SLCO1B1 c.521T→C SNP does not affect the pharmacokinetics of rosiglitazone or pioglitazone, indicating that OATP1B1 plays no significant role in the disposition of these drugs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• A common single nucleotide polymorphism (SNP) (c.521T→C) of the SLCO1B1 gene, encoding the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1, has been associated with marked changes in the pharmacokinetics of the antidiabetic drug repaglinide.
• Rosiglitazone and pioglitazone are competitive inhibitors of OATP1B1 and might thus be its substrates.
• Gemfibrozil, an inhibitor of OATP1B1 in vitro, considerably increases the plasma concentrations of rosiglitazone and pioglitazone in vivo in humans.

WHAT THIS STUDY ADDS

• The SLCO1B1 c.521T→C SNP was not associated with changes in rosiglitazone or pioglitazone pharmacokinetics in healthy volunteers.
• OATP1B1 is thus unlikely to play an important role in the disposition of rosiglitazone or pioglitazone.

     

Development of population PK model with enterohepatic circulation for mycophenolic acid in patients with childhood-onset systemic lupus erythematosus

AIM

This study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood-onset systemic lupus erythematosus (cSLE).

METHODS

MPA concentration–time data were from outpatients on stable oral mycophenolate mofetil (MMF) and collected under fasting conditions, with standardized meals (1 and 4 h post-dose). Sampling times were pre-dose, 20, 40 min, 1, 1.5, 2, 3, 4, 6 and 9 h, post dose. The population PK analysis simultaneously modelled MPA and 7-O-MPA-β-glucuronide (MPAG) concentrations using nonlinear mixed effect modelling.

RESULTS

PK analysis included 186 MPA and MPAG concentrations (mg l^–1) from 19 patients. cSLE patients, age range 10–28 years, median 16.5 years were included. Mean ± SD disease duration was 3.8 ± 3.7 years. The final PK model included a gallbladder compartment for enterohepatic recycling and bile release time related to meal times, with first order absorption and single series of transit compartments. The PK estimates for MPA were CL₁/F 25.3 l h^–1, V₃/F 20.9 l, V₄/F 234 l and CL₂/F 19.8 l h^–1.

CONCLUSION

The final model fitted the complex processes of absorption and enterohepatic circulation (EHC) in those treated with MMF for cSLE and could be applied in Bayesian dose optimization algorithms.     

Polymorphisms of VEGFA gene and susceptibility to hemorrhage risk of brain arteriovenous malformations in a Chinese population

Aim:

To evaluate the influence of the vascular endothelial growth factor A (VEGFA) polymorphisms on risk of presentation with intracerebral hemorrhage (ICH).

Methods:

Nine selected VEGFA single-nucleotide polymorphisms (SNPs) were genotyped in 311 patients with brain arteriovenous malformations (BAVM) in a Chinese population. Associations between individual SNPs/haplotypes and the hemorrhage risk of BAVMs were evaluated using logistic regression analysis.

Results:

In the single-locus analysis, rs1547651 was associated with increased risk of ICH (adjusted OR=2.11, 95% CI=1.01–4.42 compared with the AA genotype). In particular, an increased risk for ICH was associated with this variant in female patients (adjusted OR=3.21, and 95% CI=0.99–10.36). Haplotype-based analyses revealed that haplotype ''GC'' in block 1 and haplotype ''ACC'' in block 2 were associated with a 30%–38% reduction in the risk of ICH in patients with BAVMs compared to the most common haplotype (P_sim=0.033 and P_sim=0.005, respectively). The protective effect of haplotype ''ACC'' in block 2 was more evident in male patients and subjects with BAVMs of a size ≥3 cm (adjusted OR=0.57, 95% CI=0.34–0.97 and adjusted OR=0.57, 95% CI=0.31–0.86, respectively).

Conclusion:

The results suggest that VEGFA gene variants may contribute to ICH risk of BAVM.     

A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects

AIM

Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects.

METHODS

Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration−time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1.

RESULTS

The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis–Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day⁻¹ and 0.14 l day⁻¹, respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day⁻¹ and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml⁻¹. Interindividual variability of model parameters was moderate, ranging from 13.6% (V_max) to 49.8% (Q).

CONCLUSION

The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.     

Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males

AIMS

Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males.

METHODS

In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20–46 years) in each panel received single oral doses of 5–400 mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0–48 h post dose and plasma DPP-4 inhibition from 0–24 h post dose. The results were compared with historical data from young, healthy non-Japanese males.

RESULTS

Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2–6 h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9–14 h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73–1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50 mg resulted in weighted average DPP-4 inhibition from 0–24 h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia.

CONCLUSIONS

The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.