Jean-Francois Marier

Pharmacokinetic analysis of capsaicin after topical administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain.

Capsaicin, a pungent compound in chili peppers, is a highly selective agonist for the transient receptor potential vanilloid 1 receptor expressed in nociceptive sensory nerves. A high-concentration (640 μg/cm2) capsaicin patch, designated NGX-4010, is in clinical evaluation for the management of peripheral neuropathic pain. To determine systemic capsaicin exposure after single 60- or 90-minute NGX-4010 applications, plasma samples were collected from 173 patients with postherpetic neuralgia (PHN), painful human immunodeficiency virus-associated neuropathy (HIV-AN), and painful diabetic neuropathy (PDN). The percentages of patients with quantifiable levels of capsaicin at any time point were 31% for PHN (30 of 96), 7% for HIV-AN (3 of 44), and 3% for PDN (1 of 33). The maximum plasma concentration observed in any patient was 17.8 ng/mL. Due to the limited number of quantifiable levels, a population analysis was performed to characterize the pharmacokinetics (PK) of capsaicin. Plasma concentrations were fitted adequately using a 1-compartment model with first-order absorption and linear elimination. Capsaicin levels declined very rapidly, with a mean population elimination half-life of 1.64 hours. Mean area under the curve and Cmax values after a 60-minute application were 7.42 ng·h/mL and 1.86 ng/mL, respectively. Only a few correlations between calculated PK parameters and patient characteristics were observed. Duration and area of application of the patch were detected as significant covariates explaining the PK of capsaicin. Ninety-minute applications of NGX-4010 resulted in capsaicin area under the curve and Cmax values approximately 1.78- and 2.15-fold higher than those observed in patients treated for 60 minutes. Treatment on the feet (patients with HIV-AN and PDN) produced far lower systemic exposure than treatment on the trunk (patients with PHN). Finally, larger treatment areas were associated with statistically higher Vc/F values. The low systemic exposure and very rapid elimination half-life of capsaicin after NGX-4010 administration are unlikely to result in systemic effects and support the overall safety profile of this investigational cutaneous patch.

Phase 2 Comparison of A Novel Ammonia Scavenging Agent With Sodium Phenylbutyrate In Patients With Urea Cycle Disorders: Safety, Pharmacokinetics And Ammonia Control

UNLABELLED Glycerol phenylbutyrate (glyceryl tri (4-phenylbutyrate)) (GPB) is being studied as an alternative to sodium phenylbutyrate (NaPBA) for the treatment of urea cycle disorders (UCDs). This phase 2 study explored the hypothesis that GPB offers similar safety and ammonia control as NaPBA, which is currently approved as adjunctive therapy in the chronic management of UCDs, and examined correlates of 24-h blood ammonia. METHODS An open-label, fixed sequence switch-over study was conducted in adult UCD patients taking maintenance NaPBA. Blood ammonia and blood and urine metabolites were compared after 7 days (steady state) of TID dosing on either drug, both dosed to deliver the same amount of phenylbutyric acid (PBA). RESULTS Ten subjects completed the study. Adverse events were comparable for the two drugs; 2 subjects experienced hyperammonemic events on NaPBA while none occurred on GPB. Ammonia values on GPB were approximately 30% lower than on NaPBA (time-normalized AUC=26.2 vs. 38.4 micromol/L; Cmax=56.3 vs. 79.1 micromol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time-normalized AUC) by post hoc analysis. Systemic exposure (AUC(0-24)) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 microgh/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 microg h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 microg h/mL) were similar. Urinary PAGN excretion accounted for approximately 54% of PBA administered for both NaPBA and GPB; other metabolites accounted for <1%. Intact GPB was generally undetectable in blood and urine. Blood ammonia correlated strongly and inversely with urinary PAGN (r=-0.82; p<0.0001) but weakly or not at all with blood metabolite levels. CONCLUSIONS Safety and ammonia control with GPB appear at least equal to NaPBA. Urinary PAGN, which is stoichiometrically related to nitrogen scavenging, may be a useful biomarker for both dose selection and adjustment for optimal control of venous ammonia.

Pharmacokinetics, Safety, and Tolerability of Teduglutide, a Glucagon-Like Peptide-2 (GLP-2) Analog, Following Multiple Ascending Subcutaneous Administrations in Healthy Subjects

Teduglutide, a glucagon‐like peptide‐2 (GLP‐2) analog, is currently being evaluated for the treatment of short‐bowel syndrome, Crohns disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N =64) were assessed following daily subcutaneous administrations for 8 days in a double‐blinded, randomized, placebo‐controlled, ascending‐dose study. Teduglutide treatments were administered as a 50‐mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20‐mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once‐daily repeated administrations. The apparent clearance of teduglutide following administration of the 50‐mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20‐mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50‐mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.

Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate.

UNLABELLED Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). STUDY DESIGN Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. RESULTS Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198-476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range=192-449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24h with occasional values >100 μmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p≥0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p=0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. CONCLUSIONS These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring.

Clinical Trial Simulations in Pediatric Patients Using Realistic Covariates: Application to Teduglutide, a Glucagon‐Like Peptide‐2 Analog in Neonates and Infants With Short‐Bowel Syndrome

Teduglutide, a synthetic glucagon‐like peptide‐2 (GLP‐2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short‐bowel syndrome (SBS), Crohns disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple‐dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect.

Pharmacokinetics, Tolerability, and Performance of a Novel Matrix Transdermal Delivery System of Fentanyl Relative to the Commercially Available Reservoir Formulation in Healthy Subjects

A novel transdermal formulation of fentanyl‐containing dipropylene glycol droplets dispersed in a silicone matrix with a rate‐controlling membrane was developed. Healthy male subjects (n = 24) received repeated 72‐hour applications of fentanyl (50 μg/h) as the novel matrix and the conventional reservoir formulations in a randomized, 2‐way crossover study. Blood samples were collected, and serum concentrations of fentanyl were assayed using liquid chromatography with mass spectrometry detection. The mean area under the curve (AUCτ) and peak concentrations (Cmax) of the matrix formulation were 84 838 pg·h/mL and 1680 pg/mL, respectively. Ratio and 90% confidence intervals of AUCτ and Cmax between the 2 formulations were within 80% to 125%. Adherence of the matrix formulation was higher than the reservoir formulation (62.5 vs 56.2%, P < .0001), without affecting skin irritation. Vital signs and adverse events of the 2 formulations were similar in nature and frequency. The novel matrix formulation displayed enhanced adherence and resulted in similar pharmacokinetics and tolerability as the reservoir formulation.

Population Pharmacokinetics of Teduglutide Following Repeated Subcutanenous Administrations in Healthy Participants and in Patients With Short Bowel Syndrome and Crohn's Disease

Teduglutide is a GLP‐2 analog currently evaluated for the treatment of short bowel syndrome, Crohns disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1‐compartment model with a site‐specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of teduglutide. The elimination half‐life (t1/2) of teduglutide was also influenced by the body weight of participants. For a male patient weighing 50 and 90 kg, t1/2 of teduglutide was 0.897 and 2.99 hours, respectively. Renal and hepatic function of patients did not affect the PK of teduglutide. As a result, no dose adjustment was deemed necessary in patients with altered renal or liver function. The population PK model will help to support adequate drug labeling following SC administrations in patients and determine whether an individualized dosage is required.

Pharmacokinetics and Pharmacodynamics of TBR-652, a Novel CCR5 Antagonist, in HIV-1-Infected, Antiretroviral Treatment-Experienced, CCR5 Antagonist-Naïve Patients

ABSTRACT TBR-652 is a novel CCR5 antagonist with potent in vitro anti-HIV activity. The objective of this study was to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652 in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients. A double-blind, placebo-controlled, randomized, dose-escalating study of TBR-652 monotherapy given once daily orally for 10 days was performed, followed by a 40-day follow-up period. Approximately 10 patients/dose level received 25, 50, 75, 100, and 150 mg TBR-652 or placebo (4:1). Blood was collected at different intervals for PK and HIV-1 RNA assessments. PK analysis of TBR-652 was performed using noncompartmental methods. PK/PD was modeled using a maximum inhibitory effect model (Emax) and 50% inhibitory concentrations (IC50). TBR-652 was well absorbed in the systemic circulation. TBR-652 concentration levels declined slowly, with mean elimination half-lives ranging from 22.5 to 47.62 h across dose levels. TBR-652 treatment resulted in potent, dose-dependent decreases in viral load, with statistically significant decreases in nadir HIV-1 RNA compared to baseline for all dose levels. Suppression of HIV-1 RNA persisted over the 40-day follow-up period. A steep exposure-effect relationship was observed, with an Emax of −1.43 log10 copies/ml and IC50 of 13.1 ng/ml. TBR-652 was generally safe and well tolerated at all dose levels studied. Short-term monotherapy treatments of TBR-652 in HIV-1-infected patients resulted in promising PK and PD results, with a clear exposure-response relationship at the current dose levels studied. Data from this study support further development of TBR-652 in HIV-infected patients.

Pharmacokinetics and Efficacies of Liposomal and Conventional Formulations of Tobramycin after Intratracheal Administration in Rats with Pulmonary Burkholderia cepacia Infection

ABSTRACT The objective of the present study was to determine the pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin against Burkholderia cepacia in a model of chronic lung infection. Male Sprague-Dawley rats were inoculated intratracheally with 106 CFU of a very resistant strain of B. cepacia (strain BC 1368; MIC, 128 μg/ml) to establish lung infection. A 1,200-μg dose of tobramycin was administered intratracheally as a liposomal formulation and as a conventional formulation. Rats were anesthetized and exsanguinated by cardiac puncture at different times over 24 h to assess pulmonary tobramycin concentrations and the number of residual CFU. Pharmacokinetic parameters were calculated by using a two-compartment model with NONMEM. The mean half-life at the β phase (t1/2β) and the pulmonary exposure (the area under the concentration-time curve [AUC]) of liposomal tobramycin were 19.7 h (coefficient of variation [CV], 24.2%) and 6,811 μg · h/lungs (CV, 19.7%), respectively. The pharmacokinetics of conventional tobramycin were statistically different, with a t1/2β and AUC of 12.9 h (CV, 31.4%) and 821 μg · h/lungs (CV, 15.0%), respectively. Pearson chi-square analyses were performed on residual CFU data distributed in the following categories: <103, 103 to 105, and >105. Differences in CFU data between formulations showed a statistical trend (P < 0.10) when data from all time points were used, and statistically significant differences were found after 12 h (P < 0.05), with greater eradication achieved with the liposomal formulation. In conclusion, intratracheal administration of tobramycin in liposomes was associated with marked changes in the pharmacokinetics of the drug in the lung and an apparent trend for a prolonged efficacy against B. cepacia. These results support the hypothesis that inhalation of liposomal tobramycin may improve the management of chronic pulmonary infections caused by resistant bacteria in patients with cystic fibrosis.

Pharmacokinetics of Lamivudine, Zidovudine, and Nevirapine Administered as a Fixed-Dose Combination Formulation Versus Coadministration of the Individual Products

The pharmacokinetics of 150 mg lamivudine, 300 mg zidovudine, and 200 mg nevirapine were assessed following single oral administration of a fixed‐dose combination tablet and coadministration of the separate innovator products in healthy male subjects (n = 64) under fasting conditions in an open‐label, randomized, 2‐way crossover study. Multiple blood samples were collected up to 72 hours and plasma concentrations of antiretrovirals were assayed using liquid chromatography/tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed using an analysis of variance model. The ratio of the least squares mean (fixed‐dose combination to individual products) and 90% confidence intervals of AUC0‐t, AUC0‐∞, and Cmax for lamivudine, zidovudine, and nevirapine were all within 80.0% to 125.0%, suggesting a similar rate and extent of antiretroviral exposure in the bloodstream. Mean oral clearance (CL/F) values of lamivudine, zidovudine, and nevirapine for the fixed‐dose combination were 23.7, 127, and 1.65 L/h, respectively. The fixed‐dose combination and individual products were equally safe and well tolerated, with only a few subjects experiencing drug‐related adverse events. The current fixed‐dose combination of lamivudine, zidovudine, and nevirapine is expected to provide a similar efficacy/safety profile as coadministration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV.