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Purpose Patients with type 2 diabetes mellitus require strict blood glucose control, and combination therapy with a thiazolidinedione and dipeptidyl peptidase-4 inhibitors, such as lobeglitazone and sitagliptin, is one of the recommended treatments. The objective of this study was to investigate a possible pharmacokinetic interaction between lobeglitazone and sitagliptin after multiple oral administrations in healthy Korean men. Methods Two randomized, open-label, multiple-dose, 2-way crossover studies were conducted simultaneously in healthy men. In study 1, men were randomly assigned to 1 of 2 sequences, and 1 of the following treatments was administered in each period: 1 tablet of lobeglitazone sulfate (0.5 mg) once daily for 5 days and or 1 tablet each of lobeglitazone sulfate (0.5 mg) and sitagliptin (100 mg) once daily for 5 days. In study 2, men were also randomly assigned to 1 of 2 sequences and the treatments were as follows: 1 tablet of sitagliptin (100 mg) once daily for 5 days or 1 tablet each of sitagliptin (100 mg) and lobeglitazone sulfate (0.5 mg) once daily for 5 days. Serial blood samples were collected up to 48 h after dosing on the fifth day. Plasma drug concentrations were measured by LC-MS/MS. Pharmacokinetic parameters, including Cmax,ss and AUC0–τ , were determined by noncompartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% CIs of log-transformed Cmax,ss and AUC0–τ for separate or coadministration were calculated to evaluate pharmacokinetic interactions. Findings Nineteen men from study 1 and 17 from study 2 completed the pharmacokinetic sampling and were included in the analyses. The GLSM ratios of Cmax,ss and AUC0–τ were 0.9494 (95% CI, 0.8798–1.0243) and 1.0106 (95% CI, 0.9119–1.1198) for lobeglitazone (from study 1) and 1.1694 (95% CI, 1.0740–1.2732) and 1.0037 (95% CI, 0.9715–1.0369) for sitagliptin (from study 2), respectively. Implications Except for the slight 17% increase in the sitagliptin Cmax,ss value, the pharmacokinetic parameters of lobeglitazone and sitagliptin met the pharmacokinetic equivalent criteria when administered separately or in combination. The increase in Cmax of sitagliptin when coadministered with lobeglitazone would not be clinically significant in practice. ClinicalTrials.gov Identifier: NCT02824874 and NCT02827890 .

Purpose Coadministration of lobeglitazone and dapagliflozin is expected to result in a blood glucose–lowering effect, followed by a gradual increase, in clinical usage; however, combining drugs could cause negative interactions. This study aimed to evaluate the effect of the coadministration of lobeglitazone and dapagliflozin on their individual pharmacokinetic properties at steady state in healthy male volunteers in the fasted state. Methods This study consisted of 2 parts, each of which was a randomized, open-labeled, multiple-dose, 2-way crossover study in 20 healthy male volunteers in each part. Blood samples were taken periodically over a 48-h period after dosing to derive total plasma lobeglitazone and dapagliflozin pharmacokinetic properties; safety profile was evaluated throughout the study. Findings When the pharmacokinetic properties of dapagliflozin were evaluated following its administration alone and in combination with lobeglitazone, point estimate and 90% CI of the geometric mean ratio of dapagliflozin AUCτ were entirely within the conventional bioequivalence range of 80%–125%. However, although it was not clinically meaningful, its Css,max was ~8% lower in subjects receiving multiple doses of dapagliflozin and lobeglitazone than that in those administered dapagliflozin alone. The pharmacokinetic properties of lobeglitazone were evaluated following its administration alone and in combination with dapagliflozin. The geometric mean ratios and 90% CIs of the lobeglitazone Css,max and AUCτ were within the conventional bioequivalence range of 80%–125%. Implications Coadministration of lobeglitazone and dapagliflozin had no apparent clinically relevant effects on the pharmacokinetic properties of either drug. Based on these findings, it is anticipated that lobeglitazone and dapagliflozin can be coadministered without dose adjustment. ClinicalTrials.gov identifier: NCT03616392

A simple and sensitive chromatographic method has been developed for the quantitative analysis of an antiviral agent, daclatasvir (DCV), that commonly prescribed for the treatment of hepatitis C viral (HCV) infection. The method was applied to detect DCV in human plasma and real blood samples collected from patients diagnosed with HCV and treated with DCV. The analysis strategy was based on recording the native fluorescence of DCV in plasma, after pre-column treatment to precipitate the plasma proteins using a readily applicable protocol. Chromatographic conductions, factors influencing the fluorescence and stability studies were also investigated. Furthermore, the method was validated according to the International Conference on Harmonization (ICH) guidelines and could be used to detect DCV in plasma over a linear range of 1.0–4000 ng/mL, with an acceptable sensitivity as the limit of detection (LOD) was 0.025 ng/mL. In addition, the study was extended to evaluate the pharmacokinetic interaction between DCV and a co-prescribed antidepressant drug, fluoxetine (FLX) in real blood samples, collected from volunteering patients who were diagnosed with HCV and treated with DCV alone or combined with FLX. The results showed a significant influence of FLX on the pharmacokinetic profile of DCV. The findings observed in this study could be used by clinical pharmacists to adjust the DCV dose, when combined with FLX, during the HCV treatment.

Avanafil (AVN) is a new selective phosphodiesterase-5 (PDE-5) inhibitor, which is used as an oral treatment of erectile dysfunction. Coadministration of avanafil (AVN) with some antihypertensive drugs especially in elderly patients is a very common case. Nimodipine (NIM) is one of these hypotensive drugs that are commonly coadministered. Synergistic hypotension effect as a result of AVN and NIM coadministration is expected; therefore, it is mandatory to study the possible pharmacokinetic interaction between them. The main aim of the current work is to develop a simple, sensitive, and selective electrochemical method for simultaneous determination of AVN and NIM in human serum samples. Nickel oxide nanoparticles/poly(sulfanilamide) film was used as a new electrochemical modifier, which is electrodeposited on the surface of pencil graphite electrode (PGE) to improve its electrochemical properties. The best resolution between the two studied drugs was achieved by using Britton-Robinson buffer (BRB) at pH 3.0 producing two peaks at 1.45 V and 0.80 V for AVN and NIM, respectively. Furthermore, cyclic voltammetry was utilized for the first time to study the oxidation behavior of AVN and NIM and a plausible oxidation mechanism was suggested for both of them. The proposed square wave voltammetric method was successfully applied for trace quantification of AVN and NIM in real human serum samples with detection and quantitation limits of 0.037 and 0.10 μmol L−1 for AVN and 0.32 and 0.98 μmol L−1 for NIM, respectively. Moreover, the suggested approach was effectively implemented to investigate the possible pharmacokinetic interaction between AVN and NIM in serum samples of heathy human male volunteers. It was found from the pharmacokinetic parameters calculated for AVN when administered alone or in presence of NIM that there is a significant increase of serum concentration of AVN, when it is coadminstered with NIM, which stresses the importance of dose adjustment of AVN when coadministered with NIM.

Silymarin is a mixture of flavonolignans isolated from the fruit of milk thistle (Silybum marianum (L.) Gaertner). Milk thistle extract is the active ingredient of several medications and dietary supplements to treat liver injury/diseases. After the oral administration, flavonolignans are extensively biotransformed, resulting in the formation of sulfate and/or glucuronide metabolites. Previous studies demonstrated that silymarin components form stable complexes with serum albumin and can inhibit certain cytochrome P450 (CYP) enzymes. Nevertheless, in most of these investigations, silybin was tested; while no or only limited information is available regarding other silymarin components and metabolites. In this study, the interactions of five silymarin components (silybin A, silybin B, isosilybin A, silychristin, and 2,3-dehydrosilychristin) and their sulfate metabolites were examined with human serum albumin and CYP (2C9, 2C19, 2D6, and 3A4) enzymes. Our results demonstrate that each compound tested forms stable complexes with albumin, and certain silymarin components/metabolites can inhibit CYP enzymes. Most of the sulfate conjugates were less potent inhibitors of CYP enzymes, but 2,3-dehydrosilychristin-19-O-sulfate showed the strongest inhibitory effect on CYP3A4. Based on these observations, the simultaneous administration of high dose silymarin with medications should be carefully considered, because milk thistle flavonolignans and/or their sulfate metabolites may interfere with drug therapy.

Resume Les interactions pharmacocinetiques sont nombreuses et variees. Elles se produisent lorsqu’un medicament entraine des modifications de concentration d’un autre medicament pris simultanement, autrement dit lorsqu’il modifie sa pharmacocinetique.

Drug-drug interactions can lead to serious and potentially lethal adverse events. In recent years, several drugs have been withdrawn from the market due to interaction-related adverse events. The objective of this study was to evaluate the pharmacokinetic interaction between pioglitazone (PG) and carbamazepine (CBZ) in healthy male rabbits.A randomized, two-crossover design study was conducted in six healthy male rabbits. The study consisted of two periods: period one, when each rabbit received a single dose of 70 mg CBZ-suspension. Period two, when each rabbit received a single dose of 70 mg CBZ-suspension co-administered with a single dose of 1.5 mg PG with a washout period of one week between the two periods. Serial blood samples were collected over a period of 48 h. Chemiluminescent enzyme immunoassay (CLEIA) was used to measure CBZ in serum. Pharmacokinetic (PK) parameters Cmax, Tmax, t 1/2, AUC0-t, AUC 0-∞, and ke were determined for the two periods using non-compartmental analysis.In the two periods of treatment, Cmax, Tmax, AUC0-t, AUC0-∞, t ½ and ke for CBZ were administered alone and in combination with PG. Cmax, the mean peak plasma concentration was 4.33 ± 2.4 μg/mL versus 4.76 ± 2.1 μg/ml, tmax, time taken to reach, was 2.91 ± 1.11 h versus 3.6 ± 1.83 h, total area under the curve AUC0-t was 64.90 ± 43.6 μg·h/ml versus 102.90 ± 66.9 μg·h/ml, AUC0-∞ was 74.0 ± 52.6 μg·h/ml versus 124.3 ± 85 μg·h/mL, t ½ was 14.10 ± 2.5 h versus 16.43 ± 6.43 h and elimination rate constant ke was 0.050 ± 0.009 h(-1) versus 0.057 ± 0.049 h(-1), respectively. No statistical differences were found in pharmacokinetic of CBZ in both cases (P 0.05).The result of the study demonstrated that PG does not affect pharmacokinetic parameters of CBZ. Therefore, no cautions regarding dose or administration pattern of CBZ with PG should be taken.

The association of non-steroidal anti-inflammatory drugs with certain plant extracts can increase antinociceptive activity, permitting the use of lower doses and thus limiting side effects. Therefore, the aim objective of the current study was to examine the effects of curcumin on the nociception and pharmacokinetics of diclofenac in rats. Antinociception was assessed using the formalin test. Diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection, and a reduction in formalin-induced flinching was interpreted as an antinociceptive response. Rats were treated with oral diclofenac (1–31 mg/kg), curcumin (3.1–100 mg/kg) or the diclofenac–curcumin combination (2.4–38.4 mg/kg). To determine the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (10 mg/kg) was studied in presence and the absence of curcumin (31 mg/kg). Diclofenac, curcumin, or diclofenac–curcumin combination produced an antinociceptive effect on the formalin test. ED30 values were estimated for the individual drugs, and an isobologram was constructed. The derived theoretical ED30 for the antinociceptive effect (19.2 mg/kg) was significantly different from the observed experimental ED30 value (9.8 mg/kg); hence, the interaction between diclofenac and curcumin that mediates the antinociceptive effect was synergistic. Notwithstanding, the interaction does not appear to involve pharmacokinetic mechanisms, as oral curcumin failed to produce any significant alteration in oral diclofenac bioavailability. Data suggest that the diclofenac–curcumin combination can interact at the systemic level and may have therapeutic advantages for the clinical treatment of inflammatory pain.

The classification of drug interactions is first considered in this article, with an explanation of the terminology. Emphasis is placed on the importance of the topic in relation to the polypharmacy employed in anaesthesia and critical care. Pharmacodynamic interactions are then discussed. Further classification of these interactions is explained using examples of drugs in everyday use in anaesthesia and critical care medicine. Non-specific pharmacodynamic interactions are considered at some length, being the largest group of drug interactions that occur in anaesthesia. Synergy and summation are extremely relevant to anaesthetic practice and are employed in both induction and maintenance of anaesthesia everyday. The article then explains pharmacokinetic interactions under the headings of absorption, distribution, metabolism and elimination. Again, emphasis is placed on drugs used in current practice to highlight the relevance of each type of interaction to the reader.

Background The objective of this study was to investigate the effect of atazanavir on the pharmacodynamics and pharmacokinetics of gliclazide in rats (normal and diabetic) and rabbits to evaluate the safety and effectiveness of the combination. Methods Blood samples were analysed for blood glucose by GOD/POD method, serum gliclazide levels by HPLC method and insulin by Radio Immuno Assay method. Results In combination, atazanavir significantly enhanced the pharmacodynamic activity and altered the pharmacokinetic parameters of gliclazide in animal models. Conclusions The interaction between atazanavir and gliclazide appears to be pharmacokinetic interaction at metabolic level in animal models.

It has been reported that both liquiritigenin (LQ) and dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) have a hepatoprotective effect, and administration of both drugs together shows additive protective effect against acute liver injuries. Therefore, the pharmacokinetic interaction between LQ and DDB in rats was studied. LQ (20 and 50mg/kg for the i.v. and p.o. administration, respectively), DDB (10mg/kg for both i.v. and p.o. administration), and both drugs together were once administered intravenously or orally to rats. After the i.v. administration of both drugs together, the Cl(nr) and AUC of LQ were significantly faster (by 30.5%) and smaller (by 22.5%), respectively, than those of without DDB due to the faster hepatic blood flow rate by DDB. After the p.o. administration of both drugs together, the AUC of LQ was comparable to that of without DDB due to negligible effect of DDB on intestinal metabolism of LQ. The pharmacokinetic parameters of DDB after both i.v. and p.o. administration were not altered by LQ, indicating that LQ did not considerably affect the pharmacokinetics of DDB in rats.

This study evaluated the pharmacokinetic properties of ivermectin (IVM) and triclabendazole (TCBZ) given either separately or co-administered to sheep. Corriedale sheep received IVM alone, TCBZ alone or a combination of IVM and TCBZ intravenously. Ivermectin elimination was delayed and its plasma availability was 3-fold higher when co-administered with TCBZ. Similarly, plasma concentrations of TCBZ and its metabolites were influenced by the co-administration of IVM. Higher peak plasma concentrations of TCBZ metabolites were detected after the co-administration of TCBZ and IVM compared to those obtained following TCBZ treatment in isolation. Complementary in vitro assays were carried out to assess the influence of TCBZ on the P-glycoprotein-mediated intestinal transport of IVM, using the everted gut sac technique. Enhanced accumulation of IVM in the intestinal wall occurred after co-incubation with TCBZ. Fil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Ballent, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina Fil: Sallovitz, Juan Manuel. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentina Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentina

Resume Objectif de l'etude : Evaluation retrospective d'une cohorte de patients infectes par le VIH traites par deux inhibiteurs nucleosidiques associes a une combinaison de saquinavir/ritonavir faible dose. Patients et methodes : Cohorte retrospective de tous les patients qui au mois de mars 2000 a l'hopital Foch recevaient l'association saquinavir/ritonavir faible. Reevaluation clinique et therapeutique en mars 2002. Resultats : Soixante et onze patients inclus dans la cohorte ; 53,5 % ont continue l'association saquinavir/ritonavir faible dose, 47,5 % l'ont arrete ; causes d'arret : echec immuno-virologique dans 7 cas et simplification therapeutique dans 26 cas. L'evolution immuno-virologique est similaire dans les deux groupes mais 25 % des patients ayant arrete l'association saquinavir/ritonavir faible dose ont presente un evenement indesirable lors du traitement de relais. Conclusion : L'association saquinavir/ritonavir faible dose presente une efficacite durable et est bien toleree au long cours. C'est une option therapeutique fiable dont le benefice doit etre mis en regard des options de simplification utilisant les inhibiteurs non nucleosidiques ou les tri-therapies nucleosidiques.

This study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A daily dose of PT ( 12 mgkg −1 i.v.) was given to a group of five beagle dogs for a period of 1 week. On day eight, plasma samples were serially collected over 24 h, after administration of the PT dose. PT administration was continued, along with supplementary oral VGB ( 60 mgkg −1 ) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT ( 12 mgkg −1 , i.v.)–GBP (300 mg caps., p.o.) study on a separate group ( n = 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parenteral PT. However VGB markedly changed the drug’s kinetics, as evidenced by a 31% ( P = 0.015) reduction in total body clearance (CL) and an increase of over 45% in half-life ( t 1/2 ), ( P = 0.013) and area under the plasma PT concentration–time curve (AUC), ( P = 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in a marked reduction in systemic clearance of the latter in the dog.

Background Sirolimus, a new immunosuppressive agent, has recently been approved in the United States for use in combination with cyclosporine and corticosteroids in renal allograft transplantation. Therapeutic drug monitoring (TDM) of sirolimus is advocated by the drug's manufacturer in certain patient populations. Given the known pharmacokinetic interaction of sirolimus with cyclosporine and the requirement for patient compliance, physicians may wish to monitor steady-state trough levels of this agent. Several types of analytical methods have been investigated for use in TDM of sirolimus: immunoassay, high-performance liquid chromatography with ultraviolet detection (HPLC-UV), and HPLC with mass-spectrometric detection (HPLC-MS or HPLC/MS/MS). Objective This review identifies analytical parameters that are critical to clinical TDM of sirolimus when HPLC-UV is used. Methods Extraction of sirolimus from whole blood was performed using either liquid-liquid or solid phase techniques, whereas liquid chromatography was performed on reverse-phase analytical columns. The drug was detected at its UV extinction maximum. Calculated analytical parameters were evaluated according to current industry standards. Results HPLC-UV methods for the quantification of sirolimus meet or exceed industry standards of performance for clinical TDM. Comparison of the sirolimus levels in clinical samples analyzed by both HPLC-UV and HPLC/MS/MS indicated that the methods provided similar results. Conclusion HPLC-UV methods, although they use a less-sophisticated mode of detection than HPLC-MS or HPLC/MS/MS methods, provide an alternative means of performing TDM without sacrificing the analytical performance required for clinical monitoring of sirolimus.

Se ha descrito que la administración de antibióticos carbapenémicos puede producir la disminución de las concentraciones plasmáticas de ácido valproico (VPA). El mecanismo por el que se produce esta interacción farmacocinética no está claro, a pesar de los estudios publicados en modelos animales. Dada la interacción, se aconseja la monitorización de concentración y la sustitución, siempre que sea posible, del VPA por otro antiepiléptico o del carbapenem por un antibiótico de otro grupo.Se describen los casos de 2 niños epilépticos que recibieron simultáneamente meropenem y VPA y en los que se observa una disminución de las concentraciones plasmáticas de VPA hasta niveles subterapéuticos. Se recogen los mecanismos propuestos para la interacción y los casos publicados hasta la fecha. : Several reports have described a decrease in valproic acid (VPA) serum concentrations when carbapenem therapy is administered. The exact mechanism of this pharmacokinetic interaction is unknown, although several experimental studies have been carried out in animals. Because of these interactions, plasma concentrations of VPA in these patients should be monitored and, whenever possible, VPA or carbapenem therapy should be substituted by other drugs.We describe the cases of two epileptic children who simultaneously received meropenem and VPA. Concentrations of VPA decreased to subtherapeutic levels. We review the various mechanisms for this interaction proposed to date, as well as all reported cases.

Se ha descrito que la administracion de antibioticos carbapenemicos puede producir la disminucion de las concentraciones plasmaticas de acido valproico (VPA). El mecanismo por el que se produce esta interaccion farmacocinetica no esta claro, a pesar de los estudios publicados en modelos animales. Dada la interaccion, se aconseja la monitorizacion de concentracion y la sustitucion, siempre que sea posible, del VPA por otro antiepileptico o del carbapenem por un antibiotico de otro grupo. Se describen los casos de 2 ninos epilepticos que recibieron simultaneamente meropenem y VPA y en los que se observa una disminucion de las concentraciones plasmaticas de VPA hasta niveles subterapeuticos. Se recogen los mecanismos propuestos para la interaccion y los casos publicados hasta la fecha.

Several antibiotics have been implicated in oral contraception failure when they are administered at the same time as the oral contraceptive (OC) pill. In the present paper, a study about amoxicillin-ethinylestradiol (EE2) pharmacokinetic potential interaction was studied. Two rabbit groups were utilized, the first group received amoxicillin (10 mg/kg) and EE2 (30, 50 and 100 micrograms/kg, respectively), both by intravenous (i.v.) route. The second group received amoxicillin (oral route, 10 mg/kg/day) and EE2 (i.v. route, 100 mu/kg) on day 1, 4 and 8 of antibiotic treatment, respectively. After compartmental (two-compartment open model) and non-compartmental analysis of plasma concentrations, the statistical study (ANOVA por = 0.05) revealed that the presence of amoxicillin did not modify the EE2 distribution and elimination pharmacokinetic parameters (by comparison with those obtained in a previous study where EE2 was administered alone). There also were no significant differences with the time of amoxicillin oral treatment.

Protease Inhibitor Telaprevir Rolf van Heeswijk,1 Ann Vandevoorde,1 Peter Verboven,2 Griet Boogaerts,1 Els De Paepe,1 Rodica van Solingen-Ristea,1 Varun Garg,3 Maria Beumont1 1Tibotec BVBA, Beerse, Belgium; 2Janssen Research and Development, Beerse, Belgium; 3Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA Poster 1244 Abstract 654 Corresponding author: Rolf van Heeswijk Tibotec BVBA Turnhoutseweg 3

P1187 A CONCENTRATION-DEPENDENT PHARMACOKINETIC INTERACTION WITH TELAPREVIR INCREASES RIBAVIRIN CONCENTRATIONS AND LEADS TO HIGHER HAEMOGLOBIN DROP A. De Nicolo, A. Ciancio, L. Boglione, A. Mohamed Abdi, A. Smedile, G.P. Caviglia, G. Di Perri, M. Rizzetto, A. D’Avolio. Medical Sciences, Unit of Infectious Deseases, University of Turin, Medical Sciences, University of Turin, Gastroenterology, Turin, Italy E-mail: amedeo.denicolo@unito.it

Background: This study evaluated the potential for a pharmacokinetic (PK) interaction when sovaprevir (formerly ACH-1625), a novel NS3 HCV protease inhibitor, and ACH-3102, a second generation NS5A inhibitor, were coadministered. Sovaprevir was administered as an oral tablet, while ACH-3102 was administered as an oral liquid-filled capsule (LFC). This study also investigated whether a PK interaction existed between sovaprevir and the excipients of the ACH-3102 LFC. Methods: Twenty-four (24) healthy volunteers were divided into 4 groups. Subjects in Groups 1 (n=6) and 2 (n=6) each received a single 300 mg dose of sovaprevir with a standard meal on Day 1, followed by a washout period (Days 2 to 4), and then a single 300 mg dose of sovaprevir, co-administered with either 300 mg ACH-3102 LFC (Group 1) or placebo (Group 2) while fed a standard meal (Day 5). Subjects in Groups 3 (n=6) and 4 (n=6) each received a single 300 mg dose of sovaprevir while fasted on Day 1, followed by a washout period (Days 2 to4), and then a single 300 mg dose of sovaprevir co-administered with either 300 mg ACH3102 LFC (Group 3) or placebo (Group 4) while fasted (Day 5). Results: For sovaprevir, the respective mean Day 5/Day 1 ratios (coadministered with ACH- 3102 versus dosed alone) of Cmax, AUC(0-24) and AUC(O-∞) were 0.96, 1.05 and 1.05 when fed, and 0.89, 0.77 and 0.77 when fasted. Similarly, for sovaprevir, the respective mean Day 5/Day 1 ratios (co-administered with placebo for ACH-3102 LFC versus dosed alone) of Cmax, AUC(0-24) and AUC(O-∞) were 0.84, 0.91 and 0.90 when fed, and 1.17, 1.12 and 1.08 when fasted. Mean observed Cmax, AUC(0-24) and AUC(0-192) of ACH-3102 when coadministered with sovaprevir were all within approximately 25% of values from previous studies. Conclusions: No clinically significant change was observed in the PK of either sovaprevir or ACH-3102 when co-administered in either the fed or fasted state. No clinically significant change was observed in the PK of sovaprevir when coadministered with the excipients of the ACH-3102 LFC. Co-administration of the two agents was safe and well-tolerated.

The elimination constants and half lives of 1,2,3,7,8-, 2,3,4,7,8-PnCDF and 1,2,3,6,7,8-HxCDF were determined in the liver of female Sprague Dawley rats. The possible pharmacokinetic interaction between these PCDFs was studied

Pentylenetetrazole (75 mg/kg) induced a characteristic coarse body tremor (accompanied by limb extension) and hyperactivity in 4-day-old rat pups. These effects were reversed by diazepam (0.5 and 2 mg/kg) but not by CL 218, 872 (10 and 20 mg/kg) which is selective for type 1 benzodiazepine receptors. Diazepam did not affect the brain concentrations of pentylenetrazole, indicating that the reversal was not based on a pharmacokinetic interaction. Neither diazepam nor CL 218,872 had significant effects on the behavior of the rat pups, although diazepam (2 mg/kg) tended to increase locomotor activity. The results suggest that diazepam displays an anticonvulsant effect in the neonatal rat which is mediated by type 2 receptors.