Lopinavir/ritonavir population pharmacokinetics in neonates and infants

AIMS

Because of immature hepatic metabolism, lopinavir could present specific pharmacokinetics in the first weeks of life. We aimed at determining the optimal dosing regimen in neonates and infants weighing 1 to 10.5 kg.

METHODS

Lopinavir/ritonavir (LPV/r) pharmacokinetics were studied in 96 infants using a population approach.

RESULTS

A one-compartment model described LPV/r pharmacokinetics. Normalized to a 70 kg adult using allometry, clearance (CL/F) and distribution volume (V/F) estimates were 5.87 l h⁻¹ 70 kg⁻¹ and 91.7 l 70 kg⁻¹. The relative bioavailabilty, F, increased with post-menstrual age (PMA) and reached 50% of the adult value at 39.7 weeks.

CONCLUSIONS

Size and PMA explained some CL/F and V/F variability in neonates/infants. Based upon trough concentration limitations, suggested LPV/r dosing regimens were 40 mg 12 h⁻¹, 80 mg 12 h⁻¹ and 120 mg 12 h⁻¹ in the 1–2 kg, 2–6 kg and 6–10 kg group, respectively.     

Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmacodynamic simulation

AIM

To estimate the vancomycin pharmacokinetic profile in adult ICU patients and to assess vancomycin dosages for increasing the likelihood of optimal exposure.

METHODS

Five hundred and sixty-nine concentration–time data from 191 patients were analysed using a population pharmacokinetic approach (NONMEN™). External model evaluation was made in 46 additional patients. The 24 h area under the concentration–time curve (AUC(0,24 h)) was derived from the final model. Minimum inhibitory concentration (MIC) values for S. aureus were obtained from the EUCAST database. AUC(0,24 h) : MIC ≥ 400 was considered as PK/PD efficacy index. The probability of different dosages attaining the target considering different strains of S. aureus and patient subgroups was estimated with Monte Carlo simulation.

RESULTS

Vancomycin CL showed a significant dependence on patient age and renal function whereas Cr_Se > 1 mg dl⁻¹ increased V more than twofold. For our representative ICU patient, 61 years, 73 kg, Cr_Se= 1.4 mg dl⁻¹, measured CL_Cr= 74.7 ml min⁻¹, the estimated values were CL = 1.06 ml min⁻¹ kg⁻¹ and V= 2.04 l kg⁻¹. The cumulative fraction of response for a standard vancomycin dose (2 g day⁻¹) was less than 25% for VISA strains, and 33% to 95% for susceptible S. aureus, depending on patient characteristics.

CONCLUSIONS

Simulations provide useful information regarding the initial assessment of vancomycin dosing, the conventional dosing regimen probably being suboptimal in adult ICU patients. A graphic approach provides the recommended dose for any selected probability of attaining the PK/PD efficacy target or to evaluate the cumulative fraction of response for any dosing regimen in this population.     

Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non-purine selective inhibitor of xanthine oxidase

AIM

This study examined the effect of co-administration of febuxostat, an investigational urate lowering therapy, and hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat.

METHODS

Healthy subjects (36 healthy men and women) received single doses of febuxostat 80 mg alone and febuxostat 80 mg + hydrochlorothiazide 50 mg, separated by 7 days in an open-label, randomized, crossover fashion. Plasma concentrations of febuxostat and urinary and serum concentrations of uric acid were assessed.

RESULTS

Mean febuxostat C_max, AUC_(0–t), AUC_(0–∞), t_1/2,z, CL/F and V_ss/F values for regimens co-administration/febuxostat alone were 2.9/2.9 µg ml⁻¹, 9.3/9.1 µg ml⁻¹ h, 9.6/9.3 µg ml⁻¹ h, 6.5/6.1 h, 8.8/9.3 l h⁻¹ and 45/44 l, respectively. Geometric mean ratios (co-administration : febuxostat alone) and their 90% confidence intervals for febuxostat plasma C_max, AUC_(0–t), and AUC_(0–∞) were 1.00 (0.86, 1.17), 1.03 (0.98, 1.09), and 1.04 (0.98, 1.10), respectively; all of the 90% CIs were within the no effect range of 0.8 to 1.25. Serum uric acid C_mean,24h, C_mean,48h and CL_R for both regimens co-administration/febuxostat alone were 216/203 µmol l⁻¹, 218/202 µmol l⁻¹ and 9.1/10.1 ml min⁻¹, respectively. Although serum uric acid C_mean,24h and C_mean,48h values were higher and CL_R values lower after co-administration compared with dosing of febuxostat alone, with the differences being statistically significant (P < 0.003), none of the differences (6.5%–9.5%) was considered clinically significant.

CONCLUSION

Dose adjustment for febuxostat is not necessary when it is administered with hydrochlorothiazide.     

An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study

AIMS

To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.

METHODS

Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg⁻¹ of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.

RESULTS

Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h⁻¹ (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)^1.49. AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l⁻¹ h (or AUC3D < 900 mg l⁻¹ h) and in 91% when AUC1D > 600 mg l⁻¹ h (or AUC3D > 900 mg l⁻¹ h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.

CONCLUSIONS

To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg⁻¹ for neonates younger than 70 h, 14, 7, 7 mg kg⁻¹ for neonates between 70 and 108 h and 18, 9, 9 mg kg⁻¹ for neonates between 108 and 180 h.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates.
• Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age.

WHAT THIS STUDY ADDS

• A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen.
• Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age.
• A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced.
• Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates.

     

Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

AIMS

This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen.

METHODS

The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package.

RESULTS

Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h⁻¹ 70 kg⁻¹. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (V_ss) was 8.1 l 70 kg⁻¹. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations.

CONCLUSIONS

Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants.     

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.     

Variability in the pharmacokinetics of intravenous busulphan given as a single daily dose to paediatric blood or marrow transplant recipients

AIM

To examine inter- and intrapatient variability in the pharmacokinetics of intravenous (i.v.) busulphan given as a single daily dose to children with malignant (n = 19) and nonmalignant (n = 21) disease.

METHODS

Busulphan (120 mg m⁻², 130 mg m⁻² or 3.2 mg kg⁻¹) was administered over median 2.1 h. Blood samples (4–10) were collected after the first dose, busulphan concentrations were measured and pharmacokinetic parameters, including clearance (CL) and area under the concentration–time curve (AUC), were determined using the Kinetica software (Innaphase). Interpatient variability was assessed as percent coefficient of variation (% CV). Intrapatient variability was assessed by calculating percent differences between observed full dose AUC and AUC predicted from an initial 65 mg m⁻² dose in 13 children who had busulphan pharmacokinetic monitoring.

RESULTS

Clearance of i.v. busulphan in 40 children was 4.78 ± 2.93 l h⁻¹ (% CV 61%), 0.23 ± 0.08 l h⁻¹ kg⁻¹ (% CV 35%) and 5.79 ± 1.59 l h⁻¹ m⁻² (% CV 27%). Age correlated significantly (p < 0.001) with CL (l h⁻¹) and CL (l h⁻¹ kg⁻¹), but not with CL (l h⁻¹ m⁻²). AUC normalized to the 130 mg m⁻² dose ranged from 14.1 to 56.3 mg l⁻¹.h (% CV 37%) and also did not correlate with age. Interpatient variability in CL (l h⁻¹ m⁻²) was highest in six children with immune deficiencies (60%) and lowest in seven children with solid tumours (14%). Intrapatient variability was <13% for nine (of 13) children, but between 20 and 44% for four children.

CONCLUSIONS

There is considerable inter- and intrapatient variability in i.v. busulphan CL (l h⁻¹ m⁻²) and exposure that is unrelated to age, especially in children with immune deficiencies. These results suggest that monitoring of i.v. busulphan pharmacokinetics is required.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetics of oral busulphan given four times daily has been extensively studied.
• Large inter- and intravariability in oral busulphan exposure has led to attempts at pharmacokinetic monitoring.
• However, there have been limitations in the pharmacokinetic analysis due to inadequate characterization of the elimination phase in a 6-h dosing interval, due to late absorption in some patients.
• Intravenous (i.v.) busulphan is a relatively new administration method and there have been relatively few studies on the pharmacokinetics of i.v. busulphan, especially when given as a single daily dose.

WHAT THIS STUDY ADDS

• Inter- and intrapatient variability in i.v. busulphan pharmacokinetics is comparable to that previously observed with oral busulphan, suggesting that pharmacokinetic monitoring is advisable.
• Children with immune deficiencies, in particular, have widely variable exposure.

     

Differential effect of opioid and cannabinoid receptor blockade on heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats

BACKGROUND AND PURPOSE

Opioids and cannabinoids interact in drug addiction and relapse. We investigated the effect of the opioid receptor antagonist naloxone and/or the cannabinoid CB₁ receptor antagonist rimonabant on cannabinoid-induced reinstatement of heroin seeking and on cannabinoid substitution in heroin-abstinent rats.

EXPERIMENTAL APPROACH

Rats were trained to self-administer heroin (30 µg·kg⁻¹ per infusion) under a fixed-ratio 1 reinforcement schedule. After extinction of self-administration (SA) behaviour, we confirmed the effect of naloxone (0.1–1 mg·kg⁻¹) and rimonabant (0.3–3 mg·kg⁻¹) on the reinstatement of heroin seeking induced by priming with the CB₁ receptor agonist WIN55,212-2 (WIN, 0.15–0.3 mg·kg⁻¹). Then, in a parallel set of heroin-trained rats, we evaluated whether WIN (12.5 µg·kg⁻¹ per infusion) SA substituted for heroin SA after different periods of extinction. In groups of rats in which substitution occurred, we studied the effect of both antagonists on cannabinoid intake.

KEY RESULTS

Cannabinoid-induced reinstatement of heroin seeking was significantly attenuated by naloxone (1 mg·kg⁻¹) and rimonabant (3 mg·kg⁻¹) and fully blocked by co-administration of sub-threshold doses of the two antagonists. Moreover, contrary to immediate (1 day) or delayed (90 days) drug substitution, rats readily self-administered WIN when access was given after 7, 14 or 21 days of extinction from heroin, and showed a response rate that was positively correlated with the extinction period. In these animals, cannabinoid intake was increased by naloxone (1 mg·kg⁻¹) and decreased by rimonabant (3 mg·kg⁻¹).

CONCLUSIONS AND IMPLICATIONS

Our findings extend previous research on the crosstalk between cannabinoid and opioid receptors in relapse mechanisms, which suggests a differential role in heroin-seeking reinstatement and cannabinoid substitution in heroin-abstinent rats.

LINKED ARTICLES

This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7     

Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT1A receptor antagonist and potential novel antidepressant

Background and purpose

As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT_1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT_1A receptor antagonist activities, was evaluated in preclinical models.

Experimental approach

Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.

Key results

WAY-211612 inhibited 5-HT reuptake (K_i = 1.5 nmol·L⁻¹; K_B = 17.7 nmol·L⁻¹) and exhibited full 5-HT_1A receptor antagonist activity (K_i = 1.2 nmol·L⁻¹; K_B = 6.3 nmol·L⁻¹; I_max 100% in adenyl cyclase assays; K_B = 19.8 nmol·L⁻¹; I_max 100% in GTPγS). WAY-211612 (3 and 30 mg·kg⁻¹, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT_1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg⁻¹, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg⁻¹, s.c.) and a 5-HT_1A antagonist (WAY-100635; 0.3 mg·kg⁻¹, s.c). WAY-211612 (3.3–30 mg·kg⁻¹, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg⁻¹, i.p. and 10–56 mg·kg⁻¹, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg⁻¹, i.p.) in the rat scheduled-induced polydipsia model.

Conclusions and implications

These findings suggest that WAY-211612 may represent a novel antidepressant.     

Pyrazinamide blood concentrations in children suffering from tuberculosis: a comparative study at two doses

Aims

To evaluate the pharmacokinetics and pharmacodynamic indices of pyrazinamide at doses of 15 and 25 mg kg⁻¹ in children suffering from tuberculosis.

Methods

Twenty children with tuberculosis received pyrazinamide at a single dose of 25 mg kg⁻¹ (group I) and 15 mg kg⁻¹ (group II). Serial blood samples were collected and the drug concentrations were analyzed spectrophotometrically. The pharmacokinetic parameters were calculated and the duration of time for which pyrazinamide concentrations in serum remained above the pyrazinamide inhibitory concentrations of 20 μg ml⁻¹ and 25 μg ml⁻¹ was studied.

Results

The mean peak serum concentration was 42.4 ± 3.3 μg ml⁻¹ (95% CI ± 6.5) and 38.6 ± 3.9 μg ml⁻¹ (95% CI ± 7.7) in groups I and II, respectively. The elimination half-life was 9.3 ± 1.3 h and 10.5 ± 2.3 h (P = 0.6) and clearance was 0.06 ± 0.01 l h⁻¹ kg⁻¹ and 0.04 ± 0.01 l h⁻¹ kg⁻¹ (P = 0.08) in groups I and II, respectively. Pharmacokinetic parameters and PKPD indices were comparable with both the doses.

Conclusions

The study indicates that comparable serum concentrations of pyrazinamide are attained with 25 mg kg⁻¹ and 15 mg kg⁻¹ doses in children. The elimination half-life was longer and volume of distribution greater in children than in the adult population.

What is already known about this subject

• Pyrazinamide is recommended in doses varying from 15 to 40 mg kg⁻¹. The most commonly used average daily dose is 25 mg kg⁻¹. Its use is associated with dose dependent hepatotoxicity.
• Lower doses are not used because of lack of pharmacokinetic data especially in children. There is only one detailed study of pyrazinamide in children at a dose of 35 mg kg⁻¹.

What this study adds

• This is the first study evaluating serum concentrations of pyrazinamide in children at a dose of 15 mg kg⁻¹ which is on the lower side of the recommended dose. The study also compared the serum concentrations and pharmacokinetics achieved with this dose with the widely used dose of 25 mg kg⁻¹ in children suffering from tuberculosis.
• The pharmacokinetics and pharmacodynamic indices of pyrazinamide were comparable with the 25 and 15 mg kg⁻¹ doses.

     

Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis

BACKGROUNDS AND PURPOSE

Lactic acidosis is a fatal adverse effect of metformin, but the risk factor remains unclear. Multidrug and toxin extrusion 1 (MATE1) is expressed in the luminal membrane of the kidney and liver. MATE1 was revealed to be responsible for the tubular and biliary secretion of metformin. Therefore, some MATE polymorphisms, that cause it to function abnormally, are hypothesized to induce lactic acidosis. The purpose of this study is to clarify the association between MATE dysfunction and metformin-induced lactic acidosis.

EXPERIMENTAL APPROACH

Blood lactate, pH and bicarbonate ion (HCO₃^-) levels were evaluated during continuous administration of 3 mg·mL⁻¹ metformin in drinking water using Mate1 knockout (−/−), heterozygous (+/−) and wild-type (+/+) mice. To determine the tissue accumulation of metformin, mice were given 400 mg·kg⁻¹ metformin orally. Furthermore, blood lactate data were obtained from diabetic patients given metformin.

KEY RESULTS

Seven days after metformin administration in drinking water, significantly higher blood lactate, lower pH and HCO₃^- levels were observed in Mate1^−/− mice, but not in Mate1^+/− mice. The blood lactate levels were not affected in patients with the heterozygous MATE variant (MATE1-L125F, MATE1-G64D, MATE2-K-G211V). Sixty minutes after metformin administration (400 mg·kg⁻¹, p.o.) the hepatic concentration of metformin was markedly higher in Mate1^−/− mice than in Mate1^+/+ mice.

CONCLUSION AND IMPLICATIONS

MATE1 dysfunction caused a marked elevation in the metformin concentration in the liver and led to lactic acidosis, suggesting that the homozygous MATE1 variant could be one of the risk factors for metformin-induced lactic acidosis.     

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.

     

A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects

AIMS

To evaluate the pharmacokinetics (PK) of five H₁ receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg).

METHODS

Five H₁ receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy.

RESULTS

The median clearance (CL), apparent volume of distribution (V_d) and apparent terminal elimination half-life (t_1/2) of diphenhydramine after an i.v. microdose were 24.7 l h⁻¹, 302 l and 9.3 h, and the oral C_max and AUC_0–∞ were 0.195 ng ml⁻¹ and 1.52 ng h ml⁻¹, respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2.

CONCLUSIONS

Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.     

Reduced signal transduction by 5-HT4 receptors after long-term venlafaxine treatment in rats

BACKGROUND AND PURPOSE

The 5-HT₄ receptor may be a target for antidepressant drugs. Here we have examined the effects of the dual antidepressant, venlafaxine, on 5-HT₄ receptor-mediated signalling events.

EXPERIMENTAL APPROACH

The effects of 21 days treatment (p.o.) with high (40 mg·kg⁻¹) and low (10 mg·kg⁻¹) doses of venlafaxine, were evaluated at different levels of 5-HT₄ receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg·kg⁻¹, 21 days) was also evaluated on 5-HT₄ receptor density.

KEY RESULTS

Treatment with a high dose (40 mg·kg⁻¹) of venlafaxine did not alter 5-HT₄ mRNA expression, but decreased the density of 5-HT₄ receptors in caudate-putamen (% reduction = 26 ± 6), hippocampus (% reduction = 39 ± 7 and 39 ± 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 ± 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg·kg⁻¹) while it was attenuated in rats treated with 40 mg·kg⁻¹ of venlafaxine (% reduction = 51 ± 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT₄ receptor density.

CONCLUSIONS AND IMPLICATIONS

Our data indicate a functional desensitization of 5-HT₄ receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake.     

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.     

The ��apparent clearance�� of free phenytoin in elderly vs. younger adults

AIMS

To test the hypothesis that the ‘apparent clearance’ of free phenytoin is reduced in elderly patients.

METHODS

Two separate studies were conducted comparing free phenytoin ‘apparent clearance’ in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly.

RESULTS

In the retrospective study (n = 29), free phenytoin ‘apparent clearance’ was 0.27 ± 0.04 l kg⁻¹ day⁻¹ (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 ± 0.06 l kg⁻¹ day⁻¹ (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin ‘apparent clearance’ showed a non-significant trend to being reduced in the elderly patients (0.12 ± 0.02 l kg⁻¹ day⁻¹, 95% CI 0.07, 0.17) compared with the younger cohort (0.18 ± 0.07 l kg⁻¹ day⁻¹, 95% CI 0.09, 0.26) in those not taking interacting drugs (n = 21).

CONCLUSIONS

This research does not prove the hypothesis that the ‘apparent clearance’ of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect.     

AVE8134, a novel potent PPARα agonist, improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats

Aim:

AVE8134 is a structurally novel potent PPARα agonist. The aim of this study is to investigate the efficacy of AVE8134 on lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.

Methods:

A cell based PPAR Gal4 transactivation assay was constructed for testing the activities of AVE8134 at 3 different PPAR isoforms in vitro. Transgenic human Apo A1 (hApo A1) mice and insulin-resistant ZDF rats were used to evaluate the effects of AVE8134 in vivo.

Results:

AVE8134 was a full PPARα dominated PPAR agonist (the values of EC₅₀ for human and rodent PPARα receptor were 0.01 and 0.3 μmol/L, respectively). AVE8134 was not active at PPARδ receptor. In female hApo A1 mice, AVE8134 (1–30 mg·kg⁻¹·d⁻¹, po for 12 d) dose-dependently lowered the plasma triglycerides, and increased the serum HDL-cholesterol, hApo A1 and mouse Apo E levels. In female ZDF rats, AVE8134 (3–30 mg·kg⁻¹·d⁻¹ for 2 weeks) improved insulin-sensitivity index. In pre-diabetic male ZDF rats (at the age of 7 weeks), AVE8134 (10 mg·kg⁻¹·d⁻¹ for 8 weeks) produced an anti-diabetic action comparable to rosiglitazone, without the PPARγ mediated adverse effects on body weight and heart weight. In male ZDF rats (at the age of 6 weeks), AVE8134 (20 mg·kg⁻¹·d⁻¹ for 12 weeks) increased mRNA levels of the target genes LPL and PDK4 about 20 fold in the liver, and there was no relevant effect with rosiglitazone.

Conclusion:

AVE8134 improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats.     

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 pharmacokinetic analysis of varenicline in adult smokers

AIMS

To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers.

METHODS

Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration–time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling.

RESULTS

A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h⁻¹ (10.2, 10.6); V₂/F, 337 l (309, 364); V₃/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h⁻¹ (1.39, 3.79); K_a, 1.69 h⁻¹ (1.27, 2.00); and A_lag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for K_a[70% coefficient of variation (CV)], CL/F (25% CV), and V₂/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h⁻¹ for a typical subject with normal renal function (CLcr = 100 ml min⁻¹) to 4.4 l h⁻¹ for a typical subject with severe renal impairment (CLcr = 20 ml min⁻¹), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics.

CONCLUSIONS

Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day⁻¹, which is half the recommended dose, is indicated for subjects with severe renal impairment.