The area under the effect curve as an efficacy determinant for anti-infectives.

Pharmacokinetic/pharmacodynamic (PK/PD) indices making use of area under the curve, maximum concentration, and the duration that in vivo drug concentration is maintained above a critical level are commonly applied to clinical dose prediction from animal efficacy experiments in the infectious disease arena. These indices make suboptimal use of the nonclinical data, and the prediction depends on the shape of the PK profiles in the animals, determined by the species-specific absorption, distribution, metabolism, and elimination properties, and the dosing regimen used in the efficacy experiments. Motivated by the principle that efficacy is driven by pharmacology, we conducted simulations using a generalized pathogen dynamic model, to assess the properties of an alternative efficacy predictor: the area under the effect curve (AUEC), computed using in vitro PD and in vivo PK. Across a wide range of hypothetical scenarios, the AUEC consistently showed regimen-independent strong correlation (R2 0.76-0.98) with in vivo efficacy, superior to all other indices. These findings serve as proof of concept that AUEC should be considered in practice as a translation tool for cross-species dose prediction. Using AUEC for clinical dose prediction could also potentially cut down animal use by reducing or avoiding dose fractionation experiments.

A Three-Part, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Mode of Action of BC 007, Neutraliser of Pathogenic Autoantibodies Against G-Protein Coupled Receptors in Healthy, Young and Elderly Subjects.

BACKGROUND AND OBJECTIVE: BC 007 is a substance with a novel and innovative mode of action for the first-time causal treatment of chronic heart failure, associated with the occurrence of autoantibodies against the ß1-adrenoceptor, and other diseases of mostly the heart and vascular system, being accompanied by the occurrence of functionally active agonistic autoantibodies against G-protein-coupled receptors (fGPCR-AAb). The proposed mechanism of action of BC 007 is the neutralisation of these pathogenic autoantibodies which stimulate the respective receptor. To evaluate the safety, tolerability, pharmacokinetics and mode of action of BC 007, single intravenous infusions of increasing concentration were given to healthy young males and healthy elderly autoantibody-negative and autoantibody-positive participants of both sexes. METHODS: This study was subdivided into three parts. Part A was a single-centre, randomised, double-blind, placebo-controlled safety and tolerability study including healthy young male autoantibody-negative Whites (N = 23) and Asians (N = 1), testing doses of 15, 50 and 150 mg BC 007 (Cohorts 1-3) and elderly male and female Whites (N = 8), testing a dose of 150 mg BC 007 (Cohort 4), randomly assigned in a 3:1 ratio to BC 007 or placebo. Open-label Part B included fGPCR-AAb-positive subjects (50 and 150 mg BC 007, Cohorts 1 and 2, respectively). Open-label Part C included fGPCR-AAb-positive subjects for testing doses of 300, 450, 750, 1350 mg and 1900 mg BC 007. Lower doses were either given as an infusion or divided into a bolus plus infusion up to a dose of 300 mg followed by a constant bolus of 150 mg up to a dose of 750 mg, while at doses of 1350 mg and 1900 mg it was a slow infusion with a constant infusion rate. Infusion times increased with increasing dose from 20 min (15, 50 or 150 mg) to 40 min (300, 450 or 750 mg), 75 min (1350 mg) and 105 min (1900 mg). RESULTS: The mean observed BC 007 area under the concentration-time curve (AUC0-24) increased with increasing dose in a dose proportional manner (slope estimate of 1.039). No serious adverse events were observed. Drug-related adverse events were predominantly the expected mild-to-moderate increase in bleeding time (aPTT), beginning with a dose of 50 mg, which paralleled the infusion and returned to normal shortly after infusion. fGPCR-AAb neutralisation efficiency increased with increasing dose and was achieved for all subjects in the last cohort. CONCLUSION: BC 007 is demonstrated to be safe and well tolerated. BC 007 neutralised fGPCR-AAb, showing a trend for a dose-response relationship in elderly healthy but fGPCR-AAb-positive subjects. CLINICALTRIALS. GOV REGISTRATION NUMBER: NCT02955420.

Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy.

The effect of PF-05089771, a selective, peripherally restricted Nav1.7 sodium channel blocker on pain due to diabetic peripheral neuropathy was investigated in a randomised, placebo and active-controlled parallel group clinical trial (NCT02215252). A 1-week placebo-run in the period was followed by a 4-week treatment period and a 1-week placebo run-out/taper-down period. Single-blind placebo was administered throughout run-in and run-out periods. Subjects were randomised to receive either PF-05089771 150 mg twice daily, pregabalin 150 mg twice daily, or placebo during the 4-week treatment period. One hundred thirty-five subjects were randomised. The primary endpoint was the average pain score derived from subjects' Numerical Rating Scale scores over the past 7 days of week 4 of the double-blind treatment period. Predefined efficacy criteria for the trial were the effect of PF-05089771 being >0.5 units better than placebo at interim analysis after completion of the first part of the study. Although a trend for a reduction in the weekly average pain score in the PF-05089771 treatment group was observed, this was not statistically significant when compared with placebo at week 4, with a mean posterior difference of -0.41 (90% credible interval: -1.00 to 0.17). The effect of PF-05089771 was smaller than that seen with pregabalin, which was statistically significant when compared with placebo at week 4, with a mean posterior difference of -0.53 (90% credible interval: -0.91 to -0.20). As predefined efficacy criteria were not met, the study did not proceed to the second part. PF-05089771 was well tolerated. Possible reasons for the modest efficacy observed with PF-05089771 are discussed.

Clinical Micro-Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of Human Nav1.7 Voltage-Dependent Sodium Channels.

BACKGROUND: The emergence of genetic data linking Nav1.7 sodium channel over- and under- expression to human pain signalling has led to an interest in the treatment of chronic pain through inhibition of Nav1.7 channels. OBJECTIVE: We describe the pharmacokinetic (PK) results of a clinical microdose study performed with four potent and selective Nav1.7 inhibitors and the subsequent modelling resulting in the selection of a single compound to explore Nav1.7 pharmacology at higher doses. METHODS: A clinical microdose study to investigate the intravenous and oral PK of four compounds (PF-05089771, PF-05150122, PF-05186462 and PF-05241328) was performed in healthy volunteers. PK parameters were derived via noncompartmental analysis. A physiologically-based PK (PBPK) model was used to predict exposure and multiples of Nav1.7 50 % inhibitory concentration (IC50) for each compound at higher doses. RESULTS: Plasma clearance, volume of distribution and bioavailability ranged from 45 to 392 mL/min/kg, 13 to 36 L/kg and 38 to 110 %, respectively. The PBPK model for PF-05089771 predicted a 1 g oral dose would be required to achieve exposures of approximately 12× Nav1.7 IC50 at maximum concentration (C max), and approximately 3× IC50 after 12 h (minimum concentration [C min] for a twice-daily regimen). Lower multiples of Nav1.7 IC50 were predicted with the same oral doses of PF-05150122, PF-05186462, and PF-05241328. In a subsequent single ascending oral dose clinical study, the predictions for PF-05089771 compared well with observed data. CONCLUSION: Based on the human PK data obtained from the microdose study and subsequent modelling, PF-05089771 provided the best opportunity to explore Nav1.7 blockade for the treatment of acute or chronic pain conditions.

In vivo occupancy of the 5-HT1A receptor by a novel pan 5-HT1(A/B/D) receptor antagonist, GSK588045, using positron emission tomography.

5-hydroxytryptamine 1 (5-HT1) receptor blockade in combination with serotonin reuptake inhibition may provide a more rapid elevation of synaptic 5-HT compared to serotonin reuptake alone, by blocking the inhibitory effect of 5-HT1 receptor activation on serotonin release. GSK588045 is a novel compound with antagonist activity at 5-HT1A/1B/1D receptors and nanomolar affinity for the serotonin transporter, which was in development for the treatment of depression and anxiety. Here we present the results of an in vivo assessment of the relationship between plasma exposure and 5-HT1A receptor occupancy. Six Cynomolgus monkeys (Macaca fascicularis) were scanned using the PET ligand [(11)C]WAY100635 before and after dosing with GSK588045 (0.03, 0.1 and 0.3 mg/kg 60 min i.v. infusion). Data was quantified using a simplified reference tissue model, with the cerebellar time-activity curve used as an input function. Plasma levels of GSK588045 were measured, and the EC50 of GSK588045 for 5-HT1A receptor occupancy was estimated. An Emax model described the relationship between the GSK588045 plasma concentration and 5-HT1A receptor occupancy data well. EC50 estimates (and 95% confidence intervals) for raphe nuclei and the frontal cortex were 6.99 (2.48 to 11.49) and 7.80 (2.84 to 12.76) ng/ml respectively. GSK588045 dose dependently blocked the signal of the PET ligand [(11)C]WAY100635, confirming its brain entry and occupancy of 5-HT1A receptors in the primate brain. The estimated EC50 at the post-synaptic heteroreceptors and somatodendritic autoreceptors is similar. 5-HT1 receptor blockade by compounds such as GSK588045 may provide a faster alternate mechanism of antidepressant and anxiolytic action than standard SSRI treatment.

Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography.

The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [(11)C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [(11)C]PE2I [N-(3-iodoprop-2E-enyl)-2ß-carbomethoxy-3ß-(4-methylphenyl)nortropane], and [(11)C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [(11)C]MRB) and in humans using [(11)C]DASB and [(11)C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose-dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo.

Occupancy of brain dopamine D3 receptors and drug craving: a translational approach.

Selective dopamine D(3) receptor (D(3)R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D(3)R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D(3)Rs (O(D(3))(R)) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [(125)I](R)-trans-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)amino] tetralin ([(125)I]7OH-PIPAT) autoradiography and [(11)C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D(3)Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between O(D(3))(R) and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and O(D(3))(R) at every time point, and 100% effect at O(D(3))(R) values 72%. In humans, a single dose of GSK598809, giving submaximal levels (72-89%) of O(D(3))(R), transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher O(D(3))(R) is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D(3)R antagonist for the treatment of substance-use disorders.

Dose-related reduction in bupropion plasma concentrations by ritonavir.

The effect of repeat oral doses of ritonavir, at high (600 mg twice daily) and low (100 mg twice daily) doses, on the pharmacokinetics of a single dose of bupropion was evaluated in healthy volunteers. Subjects received a single dose of 150 mg of bupropion on day 1 and twice-daily ritonavir from day 8 through day 30. Ritonavir was up-titrated from 300 mg twice daily to 600 mg twice daily in the high-dose ritonavir study, whereas subjects remained on 100 mg twice-daily ritonavir in low-dose ritonavir study. Subjects received a second single dose of bupropion on day 24. Serial blood samples were obtained to evaluate the pharmacokinetics of bupropion and its metabolites on days 1 and 24. Steady-state ritonavir led to a decrease of area under the curve and maximum plasma concentration of bupropion by 62% to 67% in the high-dose study and by 21% to 22% in the low-dose study, indicating a drug interaction of statistical and clinical significance, particularly at high doses of ritonavir. These studies demonstrate that the reduction of bupropion exposure by ritonavir is dose-related. Dosage adjustment of bupropion may be needed when administered with ritonavir. However, the maximum recommended daily dose of bupropion should not be exceeded.

In vitro and in vivo pharmacokinetics-pharmacodynamics of GV143253A, a novel trinem.

The aim of the present study was to characterize the pharmacokinetic-pharmacodynamic relationship of GV143253A, a novel trinem anti-methicillin-resistant Staphylococcus aureus (MRSA) agent active against gram-positive cocci, including multidrug-resistant clinical isolates. An in vitro pharmacodynamic study with methicillin-susceptible S. aureus (MSSA) and MRSA has shown that the duration of exposure to GV143253A rather than its concentration is the major determinant of the extent of bacterial killing. The in vitro findings were confirmed by use of a neutropenic murine model of thigh infection caused by MSSA ATCC 25923. From the dose-response curves, the static doses extrapolated for three different dosing intervals showed that more frequent dosing of GV143253A was more effective than less frequent dosing. A pharmacokinetic-pharmacodynamic analysis demonstrated that only the time during which the drug concentration exceeded the MIC (t>MIC) correlated with in vivo GV143253A activity. The value of t>MIC required to achieve a bacteriostatic effect in a thigh infection of neutropenic animals was 20% (95% confidence interval [CI], 18 to 22%) of the dosing interval. This result is similar to those reported in the literature for carbapenems and for GV104326A, another novel trinem compound. In addition, in order to compare the therapeutic efficacy of GV143253A to that of vancomycin in a thigh infection caused by MRSA in immunocompetent mice, suitable dosing regimens were designed on the basis of previous pharmacokinetic-pharmacodynamic findings for GV143253A and on the human pharmacokinetic profile of the glycopeptide. Although the pharmacokinetic profiles of the two agents were completely different, GV143253A showed good efficacy comparable to that of vancomycin, reducing by 4 log units the bacterial counts in the thighs of treated mice relative to untreated infected animals after 48 h of therapy. The results suggest that if the time of exposure to the pathogen above the MIC is at least 30% of the dosing interval, GV143253A could have a role in the clinical treatment of infections caused by MRSA, which is difficult to eradicate with current antibiotics.

Correlation and predictive performances of saliva and plasma nicotine concentration on tobacco withdrawal-induced craving.

AIMS: To investigate whether saliva is a useful alternative to plasma for routine monitoring of nicotine and evaluate the predictive performances of saliva and plasma concentration on craving estimated by a Tiffany Questionnaire on Smoking Urge-Brief Form. METHODS: Thirteen healthy smokers were enrolled in a randomized, two period, crossover trial. Linear and power models were evaluated to predict the plasma nicotine concentrations from the saliva measurements, whereas a population PK/PD indirect response model was used to predict craving using either saliva or plasma nicotine concentration as the independent variable. RESULTS: The results of the analysis revealed that the power model was preferred over the linear one. The bias on the predicted plasma concentrations was of 0.47 ng ml-1 with a 95% confidence interval of [-0.57, 1.52] and a precision of 5.68 ng ml-1. The placebo effect model was initially fitted to data, then the indirect response approach (with inhibition in k(in)) was used to model the craving scores using plasma and saliva nicotine concentrations as independent variables. The two indirect response PK/PD models based on saliva and plasma nicotine concentrations, adequately described the onset, extent, and duration of craving. The maximal inhibition I(max) was 0.722 and 1 for saliva and plasma concentrations while the estimated nicotine concentrations giving 50% of the maximal inhibition were 269 ng ml-1 and 24.3 ng ml-1 for saliva and plasma, respectively. CONCLUSIONS: A good correlation between plasma and saliva nicotine concentrations has been found using a power model. Comparable values of bias and precision on the model-predicted craving indicate that plasma and saliva concentration can equally well be used to predict the onset of tobacco withdrawal induced craving. Analysis of saliva definitely offers a potentially more attractive way to assess nicotine concentration values, as samples can be collected easily and noninvasively. In addition, saliva sampling avoids the pain and discomfort involved in venepuncture. In studies that assess psychological measures, such as subjective mood, blood collection could present a possible confounding factor because of the anxiety and pain that accompanies it. For these reasons saliva can reasonably be considered as the ideal sampling site for all clinical studies conducted for the evaluation of the potential activity of drugs on nicotine deprivation symptoms.