Physiologically-Based Pharmacokinetic Modeling and In Vitro-In Vivo Correlation of TV-46000 (Risperidone LAI): Prediction from Dog to Human.

The interest in the development and therapeutic application of long-acting injectable products for chronic or long-term treatments has experienced exponential growth in recent decades. TV-46000 (Uzedy, Teva) is a long-acting subcutaneous (sc) injectable formulation of risperidone, approved for the treatment of schizophrenia in adults. Following sc injection, the copolymers together with risperidone precipitate to form a sc depot under the skin to deliver therapeutic levels of risperidone over a prolonged period of either 1 month or 2 months, depending upon the dose. This work presents the strategy and the results of the physiologically-based pharmacokinetic (PBPK) modeling and establishing of in vitro-in vivo correlation (IVIVC) for the prediction of TV-46000 pharmacokinetic profile in humans, using in vitro release, intravenous (iv), and sc single-dose pharmacokinetic data in beagle dogs. The resulting simulated TV-46000 PK profile in humans showed that the shape of the predicted risperidone and its active metabolite 9-OH-risperidone PK profiles was different from the observed one, thus suggesting that the TV-46000 release profile was species-dependent and cannot be directly extrapolated from dog to human. In conclusion, while level A IVIVC cannot be claimed, this work combining PBPK and IVIVC modeling represents an interesting alternative approach for complex injectable formulations where classical methods are not applicable.

Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling-A Contribution from the ConcePTION Project.

Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for "non-lactating" adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage.

Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives.

We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED50 values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), reported and characterized here, is an MSPC analogous compound with two less aliphatic carbon atoms in its structure. As both MSPC and MBPC are chiral compounds, here, we studied the carbonic anhydrase inhibitory and anticonvulsant action of both MBPC enantiomers in comparison to those of MSPC as well as their pharmacokinetic properties. Racemic-MBPC and its enantiomers showed anticonvulsant activity in the rat maximal electroshock (MES) test with ED50 values in the range of 19-39 mg/kg. (R)-MBPC had a 65% higher clearance than its enantiomer and, consequently, a lower plasma exposure (AUC) than (S)-MSBC and racemic-MSBC. Nevertheless, (S)-MBPC had a slightly better brain permeability than (R)-MBPC with a brain-to-plasma (AUC) ratio of 1.32 (S-enantiomer), 1.49 (racemate), and 1.27 (R-enantiomer). This may contribute to its better anticonvulsant-ED50 value. The clearance of MBPC enantiomers was more enantioselective than the brain permeability and MES-ED50 values, suggesting that their anticonvulsant activity might be due to multiple mechanisms of action.

A perspective on the physicochemical and biopharmaceutic properties of marketed antiseizure drugs-From phenobarbital to cenobamate and beyond.

The success rate from first time in man to regulatory approval of central nervous system (CNS) drugs is lower than the overall success rate across all therapeutic indications (eg, cardiovascular, infectious diseases). To understand the reasons for drug-candidate failure and to capture trends in antiseizure drug (ASD) design, we have analyzed the physicochemical and biopharmaceutical properties of marketed ASDs in comparison with new ASDs in development. Our comparative analysis included molecular weight (MW), logP, polar surface area (PSA), the "Lipinski rule of five," and the CNS Multiparameter Optimization (MPO) score. LogP is the logarithm of a drug-partition coefficient (P) between n-octanol and water. PSA is the molecule's surface sum of its polar atoms. ASDs' biopharmaceutical properties were classified according to their water solubility, permeability, and route of elimination as outlined by the Biopharmaceutics Classification System (BCS) and Biopharmaceutics Drug Disposition Classification System (BDDCS). For old ASDs (1912-1990), logP, PSA, and CNS MPO values ranged between 0.4 and 2.8, 37 and 87 Å2 , and 4.4 and 6.0, respectively. For second-generation ASDs (1990-2008), PSA values ranged between 39 and 116 Å2 . However, logP values showed a difference between the lipophilic (logP = 0.3-3.21) and hydrophilic (logP = -0.6 to -2.16) ASDs. For third-generation ASDs (2008-2020), logP and PSA ranged between 0.3 and 3.5 and between 57 and 76 Å2 , respectively. The mean CNS MPO scores of all marketed ASDs were similar, ranging between 4.9 and 5.4, and were similar to those of the ASDs in development (3.5-5.8). Most ASDs belong to BCS and BDDCS classes 1 and 2. MW, logP, CNS MPO score, and PSA assess lipophilicity and correlate with antiseizure activity. To succeed, a new small-molecule ASD must have MW < 375 and PSA < 140Å2 , belong to BCS and/or BDDCS class 1 or 2, and obey the Lipinski rule of five: logP < 5, MW < 500, and <5 and <10 of hydrogen-bond donors and acceptors, respectively. The similarity in the MW, logP, and PSA values of marketed and new drugs in development indicates a conservative trend in ASD design.

Pharmacokinetic and pharmacodynamic analysis of (2S,3S)-sec-butylpropylacetamide (SPD) in rats and pigs-A CNS-active stereoisomer of SPD.

OBJECTIVES: To advance the development of (2S,3S)-sec-butylpropylacetamide (SPD) as a new treatment for acute repetitive seizures (ARS), by studying its pharmacokinetics (PK) in pigs and its PK-pharmacodynamic (PK-PD) correlation in rats. METHODS: Two (2S,3S)-SPD intramuscular formulations (FA and FB ) were administered to pigs and rats and blood samples were withdrawn at different times after dosing. Major PK parameters were estimated in both species. PD analysis was conducted in rats utilizing the maximal-electroshock seizure threshold (MEST) test. Because ARS treatment requires a rapid action, the MEST test allows comparative evaluation of (2S,3S)-SPD intramuscular injection on rat susceptibility to electroconvulsive shock at various times after dosing. RESULTS: In rats, (2S,3S)-SPD plasma exposure increased proportionally following intramuscular dosing (20, 25 and 40 mg/kg) of FA and FB . Peak plasma concentration (Cmax ) was obtained at 1-2 hours after dosing and ranged between 6.8 and 9.4 mg/L. (2S,3S)-SPD plasma concentration at 10 minutes after dosing (C10 ) ranged between 2.1 and 3.5 mg/mL, and its half-life ranged between 0.9 and 2.3 hours. The highest C10 value, which may indicate rapid activity onset, and the highest Cmax were observed following administration of FA (40 mg/kg): C10  = 3.5 mg/L and Cmax  = 9.5 mg/L. In the MEST test, (2S,3S)-SPD (20 and 60 mg/kg) significantly raised the tonic seizure threshold compared to vehicle at 4, 7, 10, and 20 minutes after dosing, with a 1.6-fold increase at 20 minutes, which coincided with (2S,3S)-SPD brain Cmax . Following intramuscular dosing of (2S,3S)-SPD (12 mg/kg) to pigs of FA and FB , a Cmax value of 0.9 mg/L was obtained 0.42 and 0.75 hours after dosing, respectively. (2S,3S)-SPD C10 was 0.27 mg/L (FA ) and 0.49 mg/L (FB ). (2S,3S)-SPD clearance, volume of distribution, and half-life were 2 L/h/kg, 18-28 L/kg, and 6.1-9.7 hours, respectively. SIGNIFICANCE: (2S,3S)-SPD demonstrated a good PK-PD correlation in the rat MEST test, with a rapid onset. (2S,3S)-SPD first PK study in pigs showed that doses >12 mg/kg are required to achieve in pigs the plasma concentrations associated with activity at the rat MEST test.

Stereoselective pharmacokinetic and pharmacodynamic analysis of a CNS-active sulphamoylphenyl carbamate derivative.

3-Methylpentyl(4-sulphamoylphenyl)carbamate (MSPC) came as the most potent compound out of a new series of carbamates composed of phenyl-ethanol or branched aliphatic alcohols, and 4-benzenesulphonamide-carbamic acid. In this study, the anticonvulsant activity and pharmacokinetics (PKs) of MSPC-two individual enantiomers were comparatively analysed in rats as well as their carbonic anhydrase (CA) inhibition. The anticonvulsant activity of MSPC enantiomers was evaluated at the rat-maximal electroshock (MES) test, and their CA inhibition evaluated. (R)-MSPC had a 29% higher clearance and consequently, a lower plasma exposure area under the curve (AUC) than (S)-MSPC and racemic-MSPC. Nevertheless, (R)-MSPC had a better brain permeability than its (S)-enantiomer with brain-to-plasma-(AUC)-ratio (BPR) of 2.07 ((R)-enantiomer), 1.85 (racemate), and 0.79 ((S)-enantiomer). As a whole body (in vivo) pharmacodynamic (PD) measure, MSPC-anticonvulsant maximal electroshock seizure (MES) activity was less enantioselective than MSPC-CA inhibition. The lack of significant differences between racemic-MSPC and its individual enantiomers suggest that their anticonvulsant activity might be due to multiple mechanisms of action.

Comparative efficacy of valnoctamide and sec-butylpropylacetamide (SPD) in terminating nerve agent-induced seizures in pediatric rats.

OBJECTIVES: Children and adults are likely to be among the casualties in a civilian nerve agent exposure. This study evaluated the efficacy of valnoctamide (racemic-VCD), sec-butylpropylacetamide (racemic-SPD), and phenobarbital for stopping nerve agent seizures in both immature and adult rats. METHODS: Female and male postnatal day (PND) 21, 28, and 70 (adult) rats, previously implanted with electroencephalography (EEG) electrodes were exposed to seizure-inducing doses of the nerve agents sarin or VX and EEG was recorded continuously. Five minutes after seizure onset, animals were treated with SPD, VCD, or phenobarbital. The up-down method was used over successive animals to determine the anticonvulsant median effective dose (ED50 ) of the drugs. RESULTS: SPD-ED50 values in the VX model were the following: PND21, 53 mg/kg (male) and 48 mg/kg (female); PND28, 108 mg/kg (male) and 43 mg/kg (female); and PND70, 101 mg/kg (male) and 40 mg/kg (female). SPD-ED50 values in the sarin model were the following: PND21, 44 mg/kg (male) and 28 mg/kg (female); PND28, 79 mg/kg (male) and 34 mg/kg (female); and PND70, 53 mg/kg (male) and 53 mg/kg (female). VCD-ED50 values in the VX model were the following: PND21, 34 mg/kg (male) and 43 mg/kg (female); PND28, 165 mg/kg (male) and 59 mg/kg (female); and PND70, 87 mg/kg (male) and 91 mg/kg (female). VCD-ED50 values in the sarin model were the following: PND21, 45 mg/kg (male), 48 mg/kg (female); PND28, 152 mg/kg (male) 79 mg/kg (female); and PND70, 97 mg/kg (male) 79 mg/kg (female). Phenobarbital-ED50 values in the VX model were the following: PND21, 43 mg/kg (male) and 18 mg/kg (female); PND28, 48 mg/kg (male) and 97 mg/kg (female). Phenobarbital-ED50 values in the sarin model were the following: PND21, 32 mg/kg (male) and 32 mg/kg (female); PND28, 58 mg/kg (male) and 97 mg/kg (female); and PND70, 65 mg/kg (female). SIGNIFICANCE: SPD and VCD demonstrated anticonvulsant activity in both immature and adult rats in the sarin- and VX-induced status epilepticus models. Phenobarbital was effective in immature rats, whereas in adult rats, higher doses were required that were accompanied by toxicity. Overall, significantly less drug was required to stop seizures in PND21 animals than in the older animals, and overall, males required higher amounts of drug than females.

Design and Comparative Evaluation of the Anticonvulsant Profile, Carbonic-Anhydrate Inhibition and Teratogenicity of Novel Carbamate Derivatives of Branched Aliphatic Carboxylic Acids with 4-Aminobenzensulfonamide.

Epilepsy is one of the most common neurological diseases, with between 34 and 76 per 100,000 people developing epilepsy annually. Epilepsy therapy for the past 100+ years is based on the use of antiepileptic drugs (AEDs). Despite the availability of more than twenty old and new AEDs, approximately 30% of patients with epilepsy are not seizure-free with the existing medications. In addition, the clinical use of the existing AEDs is restricted by their side-effects, including the teratogenicity associated with valproic acid that restricts its use in women of child-bearing age. Thus, there is an unmet clinical need to develop new, effective AEDs. In the present study, a novel class of carbamates incorporating phenethyl or branched aliphatic chains with 6-9 carbons in their side-chain, and 4-benzenesulfonamide-carbamate moieties were synthesized and evaluated for their anticonvulsant activity, teratogenicity and carbonic anhydrase (CA) inhibition. Three of the ten newly synthesized carbamates showed anticonvulsant activity in the maximal-electroshock (MES) and 6 Hz tests in rodents. In mice, 3-methyl-2-propylpentyl(4-sulfamoylphenyl)carbamate(1), 3-methyl-pentan-2-yl-(4-sulfamoylphenyl)carbamate (9) and 3-methylpentyl, (4-sulfamoylphenyl)carbamate (10) had ED50 values of 136, 31 and 14 mg/kg (MES) and 74, 53, and 80 mg/kg (6 Hz), respectively. Compound (10) had rat-MES-ED50 = 13 mg/kg and ED50 of 59 mg/kg at the mouse-corneal-kindling test. These potent carbamates (1,9,10) induced neural tube defects only at doses markedly exceeding their anticonvuslnat-ED50 values. None of these compounds were potent inhibitors of CA IV, but inhibited CA isoforms I, II and VII. The anticonvulsant properties of these compounds and particularly compound 10 make them potential candidates for further evaluation and development as new AEDs.

Design and comparative anticonvulsant activity assessment of CNS-active alkyl-carbamoyl imidazole derivatives.

A novel series of carbamoyl derivatives of alkylimidazole has been designed and their anticonvulsant activity was comparatively evaluated in the mice- and rats-maximal-electroshock (MES), subcutaneous-metrazol (scMet) seizure tests and the mice-6Hz psychomotor (6Hz) models. The ten new designed molecules contain in their chemical structure imidazole, alkyl side-chain and carbamate as three potential active moieties. In spite of the close structural features of the carbamoyl imidazole derivatives only compounds 7, 8, 13 and 16 were active at the MES test with ED50 values ranging from 12 to 20mg/kg coupled with high protective index (PI=TD50/ED50) values of 4.1-7.3 after ip administration to rats. A similar phenomenon was observed in mice where compounds 7, 8, 9, 12 had MES-ED50 values of 14-26mg/kg. Compounds 7 and 13 also demonstrated anticonvulsant activity in the 6Hz model with ED50 values of 32 and 44mg/kg, respectively. As the most active entities, compounds 7, 8 followed by 13 and 16, thus offer an optimal efficacy-safety profile and consequently, might be promising candidates for development as new antiepileptics.

Pharmacokinetic-Pharmacodynamic Correlation and Brain Penetration of sec-Butylpropylacetamide, a New CNS Drug Possessing Unique Activity against Status Epilepticus.

sec-Butylpropylacetamide (SPD) is the amide derivative of valproic acid (VPA). SPD possess a wide-spectrum anticonvulsant profile better than that of VPA and blocks status epilepticus (SE) induced by pilocarpine and organophosphates. The activity of SPD on SE is better than that of benzodiazepines (BZDs) in terms of the ability to block SE when given 20-60 min after the beginning of a seizure. However, intraperitoneal (i.p.) administration to rats cannot be extrapolated to humans. Consequently, in the current study a comparative pharmacokinetic (PK)-pharmacodynamic analysis of SPD was conducted following i.p., intramuscular (i.m.), and intravenous (i.v.) administrations to rats. SPD brain and plasma levels were quantified at various times after dosing following i.p. (60 mg/kg), i.v. (60 mg/kg), and i.m. administrations (120 mg/kg) to rats, and the major PK parameters of SPD were estimated. The antiseizure (SE) efficacies of SPD and its individual stereoisomers were assessed in the pilocarpine-induced BZD-resistant SE model following i.p. and i.m. administrations to rats at 30 min after seizure onset. The absolute bioavailabilities of SPD following i.p. and i.m. administrations were 76% (i.p.) and 96% (i.p.), and its clearance and half-life were 1.8-1.5 L h(-1) kg(-1) and 0.5-1.7 h, respectively. The SPD brain-to-plasma AUC ratios were 1.86 (i.v.), 2.31 (i.p.), and 0.77 (i.m.). Nevertheless, the ED50 values of SPD and its individual stereoisomers were almost identical in the rat pilocarpine-induced SE model following i.p. and i.m. administrations. In conclusion, in rats SPD is completely or almost completely absorbed after i.m. and i.p. administration and readily penetrates into the brain. Consequently, in spite of PK differences, the activities of SPD in the BZD-resistant SE model following i.m. and i.p. administrations are similar.