AUC0-inf Values Research Articles

Pharmacokinetics of Oleandrin Following Administration of a Nerium oleander Extract in Mice

Background. Nerium oleander Linn is native of Mediterranean regions of Africa and Europe, where it is used in folk medical practices. The whole plant is known to be toxic. Various studies have shown its antimicrobial and anticancer properties. Oleandrin, the main toxic component in Nerium oleander is an inhibitor of P-glycoprotein. Cardiac glycosides, including oleandrin, are substrates of P-glycoprotein. The presence of other inhibitors in the alcoholic extract may potentially modify the pharmacokinetics of oleandrin. Given the therapeutic potential and the associated toxicity of the alcoholic extract, it is important to investigate the kinetics of oleandrin within this extract. Purpose. The objective of this study was to determine the pharmacokinetic parameters in mice following oral and I.V. administrations of a hydroalcoholic extract of Nerium oleander. Methods. Pharmacokinetic investigations of oleandrin, a cardiotonic glycoside and main active compound in Nerium oleander, were conducted in mice following intravenous administration (30 mg/kg) and oral administration (150 mg/kg) of the hydrolcoholic extract of Nerium oleander. For the oral route, seven times were chosen for the mice sampling. Four times were chosen for the intravenous route. Three mice per group were used at each time point. In the excretion study, seven mice were housed in a mouse urine collection device and a dose of 150 mg/g was administered. A urine sample was collected after 48 hours. Oleandrin was measured by LC-MS/MS validated method. MS data were acquired in the positive ion electrospray ionization (ESI) mode. Two deuterated internal standards, cocaine-d3 and digoxin-d3, were used. The retention times were 8.47 min for oleandrin, 4.78 min for deuterated internal standard cocaine d3 and 5,37 min for deuterated internal standard digoxin d3. Results. The equivalent doses of oleandrin administred to mice were 1710 ug/kg for the oral route and 342 ug/kg for the intravenous route. Oleandrin was rapidly absorbed after oral administration (Cmax at 10 min). The AUC0-inf (ug/L*min) values obtained after intravenous and oral dosing were 34797.7 and 107222 respectively, resulting in an oral bioavailability of 61.6 %. The apparent volume of distribution (Vss) was 0.55 L/kg and Clearance ClT was 0.01 kg* L/min.

Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment.

Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose). Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment. In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone Cmax and AUC0-inf values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of Cmax and AUC0-inf values compared with healthy subjects were above 100% (138.22-176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), Cmax and AUC0-inf values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, Cmax and AUC0-inf were approximately 20-30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment. Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis.

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers.

Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50mg, 150mg, 240mg) or subcutaneously (SC; 240mg, 675mg, 1200mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. The study enrolled 49 HVs, with a median age of 39 (range 18-73)years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-timecurve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50mg IV) tested positive for ADAs at a single time point (day15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition. RO7303509 was well tolerated at single SC doses up to 1200mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. ISRCTN13175485.

First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E6742, a Dual Antagonist of Toll-like Receptors 7 and 8, in Healthy Volunteers.

The first-in-human phase I study for E6742, a dual toll-like receptor (TLR) 7 and TLR8 antagonist, has been conducted to assess the safety, tolerability, and pharmacokinetics of E6742 in healthy volunteers. In a single ascending dose (SAD) study, 42 subjects received 10-800mg of E6742 in the fasted state, as well as a 100-mg cohort in the fed state for evaluating the effect of food. In a multiple ascending dose (MAD) study, 18 subjects received 100-400mg of E6742 twice daily for 7days. E6742 was rapidly absorbed with a median tmax ranging from 1.50 to 2.50hours across dose groups under the fasted condition, and eliminated with a median t½ ranging from 2.37 to 14.4hours. After multiple oral doses, a steady state was reached by day 7. In the SAD study, dose proportionality was observed for Cmax , AUC(0-t) , and AUC(0-inf) values of E6742 up to 800mg, but these values were slightly less than dose proportional at 10mg. In the MAD study, the Cmax and AUC(0-12h)ss of E6742 appeared to be almost dose proportionally increased between 100 and 200mg, while these parameters showed more than a dose proportional increase at 400mg. In addition to safety and good tolerability, this study demonstrated cytokine concentrations in cultured peripheral blood in response to E6742 were suppressed in a dose-dependent manner. Further clinical studies targeting systemic lupus erythematosus patients are currently underway.

Pharmacokinetics of oleandrin after administration of a Nerium oleander extract in mice

to determine some pharmacokinetic parameters in mice after oral and IV administrations of hydroalcoholic extract of Nerium oleander. Pharmacokinetic studies of oleandrin, a cardiotonic glycoside and main active compound of Nerium oleander were conducted in mice after administration of an IV dose (30 mg/kg) and a PO dose (150 mg/kg) of an hydrolcoholic extract of Nerium oleander. Oleandrin was measured by LC-MS/MS. oleandrin was rapidly absorbed after oral administration (Cmax at 10 min). The AUC0-inf (ug/L*min) values obtained after IV and PO dosing were 34,797.7 and 107,222, respectively, resulting in an oral bioavailability of 61.6%. The apparent volume of distribution Vss was 0.55 L/kg and clearance ClT was 0.01 kg* L/min. Further studies are needed, to elicit the pharmacokinetic parameters of oleandrin after various routes of administration, in multiple species, multiple doses et and different preparations.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Olpasiran in Healthy Japanese and Non-Japanese Participants: Results from a Phase I, Single-dose, Open-label Study

PurposeOlpasiran, an N-acetyl galactosamine–conjugated, hepatocyte-targeted, small interfering RNA, is being developed to reduce plasma lipoprotein (Lp)-(a) concentration by directly targeting the LPA gene. This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of a single SC injection of olpasiran in healthy, Japanese and non-Japanese participants. MethodsIn this Phase I, open-label, parallel-design study, Japanese participants were randomized in a 1:1:1:1 ratio to receive a single 3, 9, 75, or 225 mg dose of olpasiran. Non-Japanese participants received a single 75 mg dose of olpasiran. The primary end points were pharmacokinetic parameters, including Cmax, AUCinf, tmax, and t1/2. Tolerability and change in Lp(a) concentration were also assessed. FindingsA total of 27 enrolled participants had a mean (SD) age of 48.0 (12.5) years. Olpasiran Cmax and AUCinf were increased in an approximately dose-proportional manner in the Japanese groups. Mean (SD) Cmax values were 242 (121.0) and 144 (71.3) ng/mL, and mean (SD) AUCinf values were 3550 (592.0) and 2620 (917.0) h·ng/mL, in the Japanese and non-Japanese groups, respectively, given 75 mg of olpasiran. Median tmax ranged from 3.0 to 9.0 hours and mean (SD) t1/2 ranged from 4.0 (0.3) to 6.9 (1.6) hours across all groups. The maximal Lp(a) reduction occurred at day 57, with mean (SD) Lp(a) percentage reductions from baseline ranging from 56.0% (21.0%) to 99.0% (0.2%). A reductions in Lp(a) was observed as early as day 4. All adverse events were mild in severity, with no serious or fatal adverse events. No clinically important changes in tolerability-related laboratory analytes or vital signs were observed. ImplicationsIn this population of healthy Japanese participants, dose-proportional increases in exposure and reduced Lp(a) in a dose-dependent manner were found with single 3, 9, 75, and 225 mg doses of olpasiran. The magnitude and durability of Lp(a) reductions were similar between the Japanese and non-Japanese groups. Olpasiran was well tolerated, with no clinically important adverse events or laboratory or vital sign abnormalities.

Common ABCB1 SNP, C3435T could affect systemic exposure of dapagliflozin in healthy subject.

P-glycoprotein (P-gp) is a transporter that plays an excretory role in epithelial cells. It is encoded by ABCB1, and single nucleotide polymorphisms (SNPs) in this gene can affect systemic drug exposure. Dapagliflozin and sitagliptin, used in type 2 diabetes treatment, are P-gp substrates. Here, we aimed to investigate whether ABCB1 polymorphisms affect dapagliflozin and sitagliptin pharmacokinetics (PK) in healthy Korean subjects. The study population consisted of 100 healthy Korean subjects (94 men and 6 women) who participated in four different clinical trials and received dapagliflozin and sitagliptin doses of 10 and 100 mg, respectively. We determined ABCB1 genotypes for the C3435T, C1236T, and G2677T/A SNPs. The relationship between the genotypes and dapagliflozin PKs was examined. Dapagliflozin and sitagliptin PK parameters were not statistically significantly affected by ABCB1 SNP genotypes. However, homozygous 3435TT subjects showed higher dapagliflozin PK parameters than CT and CC subjects. In subjects with the 3435TT and those with 3435CC and 3435CT genotypes, mean Cmax, AUCinf, and AUC0-1 values of dapagliflozin were 223.06 ng/mL and 194.81 ng /mL (p = 0.2767), 673.58 ng*h/mL and 573.96 ng*h/mL (p = 0.0492), and 128.53 ng*h/mL and 104.61 ng*h/mL (p = 0.2678), respectively. In summary, dapagliflozin and sitagliptin PK parameters were not significantly different between individuals with C1236T and C2677T/A ABCB1 genetic polymorphisms. Dapagliflozin exhibited higher systemic exposure in 3435TT subjects than in CC/CT subjects.

Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: Potential for enhanced treatment of cutaneous fungal infections

Fungal infections affect millions of people globally and are often unreceptive to conventional topical or oral preparations because of low drug bioavailability at the infection site, lack of sustained therapeutic effect, and the development of drug resistance. Amphotericin B (AmB) is one of the most potent antifungal agents. It is increasingly important since fungal co-infections associated with COVID-19 are frequently reported. AmB is only administered via injections (IV) and restricted to life-threatening infections due to its nephrotoxicity and administration-related side effects. In this work, we introduce, for the first time, dissolving microneedle patches (DMP) loaded with micronised particles of AmB to achieve localised and long-acting intradermal delivery of AmB for treatment of cutaneous fungal infections. AmB was pulverised with poly (vinyl alcohol) and poly (vinyl pyrrolidone) to form micronised particles-loaded gels, which were then cast into DMP moulds to form the tips. The mean particle size of AmB in AmB DMP tips after pulverisation was 1.67 ± 0.01 μm. This is an easy way to fabricate and load microparticles into DMP, as few steps are required, and no organic solvents are needed. AmB had no covalent chemical interaction with the excipients, but the crystallinity of AmB was reduced in the tips. AmB was completely released from the tips within 4 days in vitro. AmB DMP presented inhibition of Candida albicans (CA) and the killing rate of AmB DMP against CA biofilm inside porcine skin reached 100% within 24 h. AmB DMP were able to pierce excised neonatal porcine skin at an insertion depth of 301.34 ± 46.86 μm. Ex vivo dermatokinetic and drug deposition studies showed that AmB was mainly deposited in the dermis. An in vivo dermatokinetic study revealed that the area under curve (AUC0-inf) values of AmB DMP and IV (Fungizone® bolus injection 1 mg/kg) groups were 8823.0 d∙μg/g and 33.4 d∙μg/g, respectively (264-fold higher). AmB remained at high levels (219.07 ± 102.81 μg/g or more) in the skin until 7 days after the application of AmB DMP. Pharmacokinetic and biodistribution studies showed that AmB concentration in plasma, kidney, liver, and spleen in the AmB DMP group was significantly lower than that in the IV group. Accordingly, this system addressed the systemic side effects of intravenous injection of AmB and localised the drug inside the skin for a week. This work establishes a novel, easy and effective method for long-acting and localised intradermal drug delivery.

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Refractory Multiple Myeloma

Introduction - Elevated expression of XPO1 (Exportin 1) increases the nuclear export / inactivation of tumor suppressor proteins (e.g. p53, IkB, p21, FOXO) and promotes the export / translation of eIF4E-bound oncoprotein mRNAs (e.g. c-MYC, BCL-2, Cyclin D). Selinexor, the first oral Selective Inhibitor of Nuclear Export (SINE) compound, inhibits XPO1 and has shown promising anti-cancer activity across hematological and solid tumors in Phase 1 and 2 clinical trials, including in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Considering the breadth of knowledge on selinexor ± dexamethasone (dex) in RRMM, eltanexor (KPT-8602), a second-generation oral SINE compound, was evaluated for safety and tolerability in this pt population. The primary objectives were to determine the safety, preliminary anti-MM activity, and the recommended Phase 2 dose (RP2D) of eltanexor ± dex.Methods - In this Phase 1/2 study, using a 3+3 dose escalation design, eltanexor is dosed orally (QDx5 or QoDx3 weekly) for a 28-day cycle with a starting dose of 5 mg. Pts with less than a minor response (MR) after 1 cycle or partial response (PR) after 2 cycles were permitted to add low dose dex. In some pts, dex was added from day 1. The pharmacokinetic (PK) and pharmacodynamic (XPO1 mRNA) profiles of eltanexor were evaluated.Results - As of 31-July-2017, 36 pts (23 M/13 F; median prior therapies: 7; median age: 66) with RRMM were enrolled; most with quad- or penta-refractory MM. Median duration of treatment is 76 days (range: 10 - 441). Most common drug related adverse events (AEs; >30%, any grade) are thrombocytopenia, nausea, neutropenia, anemia, leukopenia, fatigue, diarrhea, and dysgeusia. Grade ≥3 related AEs include thrombocytopenia (43%), neutropenia (26%), leukopenia (14%), and anemia (11%). Although 2 dose limiting toxicities (DLTs; >4 missed doses and Grade 4 thrombocytopenia) were observed in different cohorts, the protocol-defined maximum tolerated dose (MTD) was not reached. Further evaluation of 20 or 30 mg eltanexor QDx5 + dex is ongoing in expansion cohorts. The preliminary efficacy of eltanexor (Table 1) shows that eltanexor ± dex can induce responses and disease stabilization. A dose proportional PK profile without accumulation has been observed. Mean Cmax and AUC0-inf values for eltanexor doses of 5 - 60 mg ranged from 36.6 - 284 ng/mL and 164 - 2,581 ng*h/mL, respectively. Tmax and t½ ranged from 0.5 - 8.0 h and 4.0 - 7.1 h, respectively. For all cohorts evaluated, the fold-change maximum (Fmax) of XPO1 mRNA expression was achieved 4 - 8 h post-dose (tmax). The Fmax for XPO1 mRNA was roughly dose proportional to the Cmax of eltanexor. As expected, based on observations with other SINE compounds, the plateau for Fmax of XPO1 mRNA in treated pts was ~6 - 10-fold change and was achievable at 40 - 60 mg of eltanexor.Conclusions - Based on preliminary data, eltanexor is well tolerated and demonstrates promising activity in this heavily pre-treated RRMM population. The gastrointestinal and constitutional toxicities observed with <40 mg eltanexor QDx5 are low grade, transient, and do not limit dosing. Thrombocytopenia (with minimal clinical impact) was the most common hematologic toxicity and was expected in this population. As with selinexor, addition of low-dose dex (20 mg) twice weekly (BIW) to the eltanexor treatment regimen appeared to improve efficacy while maintaining tolerability. Of the 31 evaluable pts, 25 received dex with their eltanexor regimen. Therefore, both 20 and 30 mg eltanexor QDx5 + 20 mg dex BIW are being evaluated to clearly define the RP2D. Based on these results and anti-tumor activity previously observed with selinexor, pts with advanced colorectal cancer, castration resistant prostate cancer, and myelodysplastic syndrome are being enrolled. [Display omitted] DisclosuresRossi:Thrassos: Consultancy; Celgene: Consultancy. Baz:Sanofi: Research Funding; BMS: Research Funding; merck: Research Funding; takeda: Research Funding; celgene: Honoraria, Research Funding; karyopharm: Research Funding. Hofmeister:Roche: Research Funding; Celgene: Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding. Shustik:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Richter:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Chen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Vogl:Teva: Consultancy; Karyopharm: Consultancy; Constellation: Research Funding; GSK: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Amgen: Consultancy; Calithera: Research Funding. Baloglu:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Pharmacokinetics of α-Pyrrolidinovalerophenone in Male Rats with and without Vaccination with an α-Pyrrolidinovalerophenone Vaccine.

α-Pyrrolidinovalerophenone (α-PVP) is a second-generation synthetic cathinone which acts as an inhibitor at the dopamine and norepinephrine transporters in the brain. These novel studies determined the pharmacokinetics (PK) of α-PVP in rats and then evaluated the effects of an α-PVP vaccine on the PK profile. Adult male Sprague-Dawley rats were randomly divided into treatment groups (n = 24/group) in which the vaccinated rats received an initial and two booster immunizations of the α-PVP vaccine at 0, 3, and 9 wks. Control rats received saline injections. α-PVP (0.56, 1, 3 mg/kg, sc) was then administered to both groups between 11-12 weeks and serum samples were collected for determination of α-PVP serum concentrations by LC-MS/MS (n=6 rats/treatment/time). At 13 weeks, brain, heart and kidney concentrations of α-PVP were determined by LC-MS/MS after administration of 1 mg/kg α-PVP (n=4-5 rats/treatment/time). PK values in control rats showed dose-dependent increases in maximum serum concentrations (Cmax) and area under the curve (AUCinf) values with an elimination half-life (t1/2) of approximately 2.1 h. α-PVP exhibited linear PK profile in control rats. Vaccinated rats had significantly (p<0.05) higher serum Cmax and AUCinf values than controls, and significantly reduced total body clearance, volume of distribution and t1/2 values. Vaccinated rats had significantly lower α-PVP concentrations in the brain, heart, and kidney in comparison to control rats at early time points. Vaccination with the novel α-PVP vaccine significantly altered serum PK leading to a time-dependent reduction in brain, kidney and heart concentrations of α-PVP compared to controls.

Prediction of plasma concentrations using in silico modelling and simulation approach: Case of Acebutolol

The aim of this study was to predict the plasma concentrations of acebutolol tablets with different dissolution profiles using computer modelling and evaluating whether they are bioequivalent using simulated population studies. The dissolution behaviour of acebutolol was studied in the USP Apparatus-II using different dissolution media for pH 1.2, 4.5, and 6.8 at 37±0.5°C. The obtained dissolution data, as well as plasma concentration-time data of the reference product from the literature were used as inputs to build pharmacokinetic model of acebutolol within GastroPlus™ software (version 9.7, Simulations Plus Inc., Lancaster, CA, USA) to simulate the in vivo profiles of the drug. The dissolution profiles of the reference product Sectral® 400mg tablets and a locally produced generic product were>85% in 15min in three dissolution media. Simulation results demonstrated that the brand and generic products would show the same in vivo performance. Population simulation results of the ln-transformed 90% confidence interval for the ratio of Cmax, AUC0-t and AUC0-inf values for the two products were within the 80-125% interval, showing to be bioequivalent. Based on the in vitro results combined with in silico simulations using GastroPlus™, a biowaiver for immediate release acebutolol tablets is justified. Furthermore, computer modelling has shown to be a very intersting tool to prove the bioequivalence for these products.

Plasma pharmacokinetics and tissue distribution of L-lysine α-oxidase from Trichoderma cf. aureoviride RIFAI VKM F- 4268D in mice.

L-lysine α-oxidase (LO) is an L-amino acid oxidase with antitumor, antimicrobial and antiviral properties. Pharmacokinetic (PK) studies were carried out by measuring LO concentration in plasma and tissue samples by enzyme immunoassay. L-lysine concentration in samples was measured spectrophotometrically using LO. After single i.v. injection of 1.0, 1.5, 3.0mg/kg the circulating T1/2 of enzyme in mice varied from 51 to 74min and the AUC0-inf values were 6.54 ± 0.46, 8.66 ± 0.59, 9.47 ± 1.45μg/ml × h, respectively. LO was distributed in tissues and determined within 48h after administration with maximal accumulation in liver and heart tissues. Mean time to reach the maximum concentration was highest for the liver-9h, kidney-1h and 15min for the tissues of heart, spleen and brain. T1/2 of LO in tissues ranged from 7.75 ± 0.73 to 26.10 ± 2.60h. In mice, plasma L-lysine decreased by 79% 15min after LO administration in dose 1.6mg/kg. The serum L-lysine levels remained very low from 1 to 9h (< 25μM, 17%), indicating an acute lack of L-lysine in animals for at least 9h. Concentration of L-lysine in serum restored only 24h after LO administration. The results of LO PK study show that it might be considered as a promising enzyme for further investigation as a potential anticancer agent.

Pharmacokinetics and bioavailability of solid dispersion formulation of tilmicosin in pigs.

Tilmicosin (TMS) is a semisynthetic macrolide antibiotic restricted to veterinary use but is only partially soluble in aqueous solutions, which limits its administration in treatments. We developed a strategy to enhance the supersaturated solubility of TMS using amorphous solid dispersion (SD). The dissolution profile shown that the dissolution rate of TMS-SD was obviously faster than TMS. The pharmacokinetics of tilmicosin (TMS) and tilmicosin solid dispersion (TMS-SD) in pigs after oral administration at a single dose of 50mg/kg b.w were investigated. The tmax of TMS-SD (2.50hr) was 1.80 times faster than TMS (4.50hr) (p<.05). There were no significant differences in the other PK parameters (Cmax , t1/2β , V/F, CL/F, MRT, and AUC0-inf ) (p>.05). The mean relative bioavailability of TMS-SD compared with TMS was 140.39%, according to the AUC0-inf values. These results demonstrated that the solid dispersion technique enhanced the bioavailability of TMS and the new formulation administered to animals via drinking water may be used as a therapeutic alternative for clinical treatments.

Pharmacokinetics of Voxelotor in Patients With Renal and Hepatic Impairment

Two open‐label studies assessed the safety, tolerability, and pharmacokinetics of Oxbryta (voxelotor) in subjects with hepatic or renal impairment. Eight subjects with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) and 8 healthy age‐, sex‐, and body mass index–matched controls were administered a single oral dose of voxelotor 900 mg. Seven patients with mild (Child‐Pugh A), moderate (Child‐Pugh B), and severe (Child‐Pugh C) hepatic impairment and healthy age‐, sex‐, and body mass index–matched controls (7:7:7:7) were administered a single oral dose of voxelotor 1500 mg, except those with severe hepatic impairment (600 mg). There was no apparent effect of renal function on the excretion of voxelotor based on comparable half‐life values between subjects with severe renal impairment and healthy matched controls. Mean area under the concentration‐time curve from time 0 to infinity (AUC0‐inf) values were lower by approximately 50% (plasma) and 25% (whole blood) in subjects with severe renal impairment compared with controls. Accordingly, dose adjustment is not required in patients with severe renal impairment. Voxelotor plasma and whole‐blood exposures were slightly increased in subjects with mild and moderate hepatic impairment. Mean AUC0‐inf values were approximately 9% to 18% higher compared with those of healthy matched controls. Dose adjustment is therefore not required in patients with mild or moderate hepatic impairment. Voxelotor mean AUC0‐inf values were approximately 90% higher in subjects with severe hepatic impairment. A lower voxelotor dose (1000 mg) is recommended for patients with severe hepatic impairment. Voxelotor was well tolerated in all treatment groups.

Development of 20(S)-Protopanaxadiol-Loaded SNEDDS Preconcentrate Using Comprehensive Phase Diagram for the Enhanced Dissolution and Oral Bioavailability

In this study, we aimed to develop a 20(S)-protopanaxadiol (PPD)-loaded self-nanoemulsifying drug delivery system (SNEDDS) preconcentrate (PSP) using comprehensive ternary phase diagrams for enhanced solubility, physical stability, dissolution, and bioavailability. Capmul MCM C8 and Capryol 90 were selected as the oil phase owing to the high solubility of PPD in these vehicles (>15%, w/w). Novel comprehensive ternary phase diagrams composed of selected oil, surfactant, and PPD were constructed, and the solubility of PPD and particle size of vehicle was indicated on them for the effective determination of PSP. PSPs were confirmed via particle size distribution, physical stability, and scanning electron microscope (SEM) with the dispersion of water. The optimized PSP (CAPRYOL90/Kolliphor EL/PPD = 54/36/10, weight%) obtained from the six possible comprehensive ternary phase diagrams showed a uniform nanoemulsion with the particle size of 125.07 ± 12.56 nm without any PPD precipitation. The PSP showed a dissolution rate of 94.69 ± 2.51% in 60 min at pH 1.2, whereas raw PPD showed negligible dissolution. In oral pharmacokinetic studies, the PSP group showed significantly higher Cmax and AUCinf values (by 1.94- and 1.81-fold, respectively) than the raw PPD group (p < 0.05). In conclusion, the PSP formulation with outstanding solubilization, dissolution, and in-vivo oral bioavailability could be suggested using effective and comprehensive ternary phase diagrams.

Development of a Physiologically Based Pharmacokinetic Model for Prediction of Pramipexole Pharmacokinetics in Parkinson's Disease Patients With Renal Impairment.

Pramipexole is the first-line medication recommended by the British National Institute for Health and Care Excellence. Pramipexole is predominantly eliminated by renal excretion. The aim was to develop a physiologically based pharmacokinetic (PBPK) model of pramipexole, providing a basis for its individualized administration. The role of glomerular filtration and organic cation transporter 2 (OCT2) in renal tubular secretion was considered. Plasma concentration-time profiles of pramipexole were predicted and validated, first in healthy populations and then in PD patients with varied renal function. Finally, the pharmacokinetics of PD patients with different degrees of renal impairment were predicted. The simulated pharmacokinetic parameters, including maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC), time to maximum plasma concentration (tmax ), and steady-state trough plasma concentration values, obtained using the PBPK model were validated using fold error values, which were all smaller than 2. The successfully validated model supported that OCT2-mediated tubular secretion was affected proportionally to changes in glomerular filtration for various degrees of renal impairment. The predicted AUC0-inf values were increased 1.16-, 1.76-, 3.26-, and 9.48-fold in mild, moderate, and severe renal impairment and end-stage renal disease (ESRD) subjects, resepctively, compared with PD patients with normal renal function. It appears that PD patients with mild renal impairment are unlikely to require dose adjustment (0.125 mg 3 times a day). The pramipexole dose should be reduced to approximately 0.125 mg twice daily, 0.125 mg once daily, and 0.0375 mg once daily in PD patients with moderate renal impairment, severe renal impairment, and ESRD, respectively.

A Phase I Comparative Pharmacokinetic and Safety Study of Two Intravenous Formulations of Vinorelbine in Patients With Advanced Non-Small Cell Lung Cancer.

Purpose: The aim of this study was to compare the pharmacokinetics and safety between two vinorelbine formulations [a new oil-in-water emulsion formulation (ANX) versus a previously marketed solution formulation (Navelbine)] in Chinese patients with advanced non-small cell lung cancer (NSCLC). Method: This was a single-center, randomized, open-label study. Eligible patients aged 18–70 years who had histologically or cytologically confirmed NSCLC were enrolled. In cycle 1, the patients alternatively received the two formulations (30 mg/m2, given as a 10-min infusion) with a 7-day interval. Samples for pharmacokinetic analysis were taken during cycle 1. For all subsequent 21-day cycles (maximum four cycles), ANX was administered on days 1 and day 8. Bioequivalence analysis was performed on Cmax, AUClast, and AUCinf. The safety profiles and anti-tumor effects were also determined. Results: From March 2013 to January 2015, 24 patients were enrolled and 20 were eligible for pharmacokinetic evaluation. The 20 subjects in the pharmacokinetic analysis set had a median age of 61 years (range, 37–70 years), and 15 patients were male (75%). Mean vinorelbine Cmax values for ANX and Navelbine were 1,317.40 and 1,446.30 ng/mL, respectively. Corresponding AUClast values were 797.08 and 924.26 ng·h/mL, respectively. AUCinf values were 830.14 and 957.16 ng·h/mL, respectively. Treatment ratios of the geometric means were 90.00% (90% CI, 83.22–99.07%) for Cmax, 86.92% (90% CI, 80.91–93.37%) for AUClast, and 87.44% (90% CI, 82.08–93.16%) for AUCinf. These results met the required 80–125% bioequivalence criteria. The most frequently reported adverse events after vinorelbine administration were neutropenia, leucopenia, neutropenic fever, and constipation. Conclusion: At therapeutic dosage levels, pharmacokinetic behavior and safety profiles were similar for both formulations. Chinese National Registry Code: ChiCTR-IPR-15005856.

Abstract 3880: In vivo activities of TP-2846: a novel tetracycline antileukemia agent

The pharmacokinetics (PK) of TP-2846 was studied in mice, rats, and monkeys via IP, PO, and IV administration. In a mouse PK study with TP-2846 dosed IP at 10 mg/kg, C max , T 1/2 , and AUC 0-inf values of 5340 ng/mL, 6.81 h, and 5944 ng•h/mL were observed, respectively. In an IV PK study in mice, TP-2846 was dosed at 1, 3, and 6 mg/kg, and the various PK parameters at each respective dose are: C max = 1142, 5881, 8518 ng/mL; T 1/2 = 6.15, 5.15, 6.92 h; AUC 0-inf = 704, 2174, 4205 ng•h/mL. In a rat PK study, TP-2846 was dosed at 5 mg/kg IV and PO. The various PK parameters by each dosing route are: C max = 7180, 4.39 ng/mL; T 1/2 = 9.64, 9.41 h; AUC 0-inf = 9390, 21.0 ng•h/mL. In a PK study in monkeys, TP-2846 was dosed at 1, 2, 4, and 6 mg/kg IV. Key PK parameters at each respective dose are: C max = 734, 1071, 1835, 2715 ng/mL; T 1/2 = 9.97, 12.5, 15.7, 22.4 h; AUC 0-inf = 4128, 8252, 19179, 30871 ng•h/mL. TP-2846 demonstrated good half-lives and exposures across all three species. Low oral bioavailability was observed when TP-2846 was dosed in rats. Dose linearity of plasma exposure was shown when varying levels of TP-2846 was dosed in mice and monkeys. The in vivo efficacy of TP-2846 was evaluated in a number of leukemia mouse xenograft models including MV4-11, MOLT-4, CCRF-CEM, HL-60, KG-1, Kasumi-1, and K-562. TP-2846 demonstrated potent in vivo efficacy in MV4-11 with a Tumor Growth Inhibition (TGI) value of 111.4% ( p = 0.001) when dosed IP at 12.5 mg/kg, QD, 4 days on/6 days off, for two cycles, while cytarabine and tigecycline had a TGI value of 23.5% and -49.2%, respectively, at their reported optimal dosing regimens. TP-2846 was also highly efficacious in HL-60 xenograft models with a TGI value of 109.1% ( p p = 1.000), 34.73% ( p = 0.643), 103.50% ( p = 0.015), and 104.87% ( p = 0.013), respectively, when dosed at 1, 2, 4, and 6 mg/kg, QDx3, for two weeks. To understand the PK parameters that drive the efficacy of TP-2846, studies with varying dosing levels and dosing schedules were conducted in the HL-60 model. Subsequent PK/PD modeling using the resulting data sets suggested that AUC is the primary efficacy driver for TP-2846 in the xenograft model. In summary, TP-2846 displayed favorable PK profiles across multiple species and demonstrated potent, dose-responding, AUC-driven efficacy in several mouse leukemia xenograft models. These data sets, combined with other desirable in vitro , in vivo , and chemical-physical properties, support the continued pre-clinical development of TP-2846 as a new antileukemia agent. Citation Format: Xiao-Yi Xiao, Cuixiang Sun, Jian Zhou, Noriaki Tatsuta, Joseph Newman, Douglas White, Barbara Hibner, Arijit Chakravarty, Jacques Dumas. In vivo activities of TP-2846: a novel tetracycline antileukemia agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3880.

Abstract 3880: In vivo activities of TP-2846: a novel tetracycline antileukemia agent

Abstract The pharmacokinetics (PK) of TP-2846 was studied in mice, rats, and monkeys via IP, PO, and IV administration. In a mouse PK study with TP-2846 dosed IP at 10 mg/kg, Cmax, T1/2, and AUC0-inf values of 5340 ng/mL, 6.81 h, and 5944 ng•h/mL were observed, respectively. In an IV PK study in mice, TP-2846 was dosed at 1, 3, and 6 mg/kg, and the various PK parameters at each respective dose are: Cmax = 1142, 5881, 8518 ng/mL; T1/2 = 6.15, 5.15, 6.92 h; AUC0-inf = 704, 2174, 4205 ng•h/mL. In a rat PK study, TP-2846 was dosed at 5 mg/kg IV and PO. The various PK parameters by each dosing route are: Cmax = 7180, 4.39 ng/mL; T1/2 = 9.64, 9.41 h; AUC0-inf = 9390, 21.0 ng•h/mL. In a PK study in monkeys, TP-2846 was dosed at 1, 2, 4, and 6 mg/kg IV. Key PK parameters at each respective dose are: Cmax = 734, 1071, 1835, 2715 ng/mL; T1/2 = 9.97, 12.5, 15.7, 22.4 h; AUC0-inf = 4128, 8252, 19179, 30871 ng•h/mL. TP-2846 demonstrated good half-lives and exposures across all three species. Low oral bioavailability was observed when TP-2846 was dosed in rats. Dose linearity of plasma exposure was shown when varying levels of TP-2846 was dosed in mice and monkeys. The in vivo efficacy of TP-2846 was evaluated in a number of leukemia mouse xenograft models including MV4-11, MOLT-4, CCRF-CEM, HL-60, KG-1, Kasumi-1, and K-562. TP-2846 demonstrated potent in vivo efficacy in MV4-11 with a Tumor Growth Inhibition (TGI) value of 111.4% (p = 0.001) when dosed IP at 12.5 mg/kg, QD, 4 days on/6 days off, for two cycles, while cytarabine and tigecycline had a TGI value of 23.5% and -49.2%, respectively, at their reported optimal dosing regimens. TP-2846 was also highly efficacious in HL-60 xenograft models with a TGI value of 109.1% (p &amp;lt; 0.001) when dosed IP at 20 mg/kg, QDx3, for two weeks. In an IV study in HL-60, TP-2846 demonstrated dose-responding antitumor efficacy with TGI values of 5.38% (p = 1.000), 34.73% (p = 0.643), 103.50% (p = 0.015), and 104.87% (p = 0.013), respectively, when dosed at 1, 2, 4, and 6 mg/kg, QDx3, for two weeks. To understand the PK parameters that drive the efficacy of TP-2846, studies with varying dosing levels and dosing schedules were conducted in the HL-60 model. Subsequent PK/PD modeling using the resulting data sets suggested that AUC is the primary efficacy driver for TP-2846 in the xenograft model. In summary, TP-2846 displayed favorable PK profiles across multiple species and demonstrated potent, dose-responding, AUC-driven efficacy in several mouse leukemia xenograft models. These data sets, combined with other desirable in vitro, in vivo, and chemical-physical properties, support the continued pre-clinical development of TP-2846 as a new antileukemia agent. Citation Format: Xiao-Yi Xiao, Cuixiang Sun, Jian Zhou, Noriaki Tatsuta, Joseph Newman, Douglas White, Barbara Hibner, Arijit Chakravarty, Jacques Dumas. In vivo activities of TP-2846: a novel tetracycline antileukemia agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3880.

Pharmacokinetic Interaction between Naloxone and Naltrexone Following Intranasal Administration to Healthy Subjects.

Naloxone (17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one HCl), a μ-opioid receptor antagonist, is administered intranasally to reverse an opioid overdose but its short half-life may necessitate subsequent doses. The addition of naltrexone [17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one], another μ-receptor antagonist, which has a reported half-life of 3 1/2 hours, may extend the available time to receive medical treatment. In a phase 1 pharmacokinetic study, healthy adults were administered naloxone and naltrexone intranasally, separately and in combination. When administered with naloxone, the C max value of naltrexone decreased 62% and the area under the concentration-time curve from time zero to infinity (AUC0-inf) decreased 38% compared with when it was given separately; lower concentrations of naltrexone were observed as early as 5 minutes postdose. In contrast, the C max and AUC0-inf values of naloxone decreased only 18% and 16%, respectively, when given with naltrexone. This apparent interaction was investigated further to determine if naloxone and naltrexone shared a transporter. Neither compound was a substrate for organic cation transporter (OCT) 1, OCT2, OCT3, OCTN1, or OCTN2. There was no evidence of the involvement of a transmembrane transporter when they were tested separately or in combination at concentrations of 10 and 500 µM using Madin-Darby canine kidney II cell monolayers at pH 7.4. The efflux ratios of naloxone and naltrexone increased to six or greater when the apical solution was pH 5.5, the approximate pH of the nasal cavity; there was no apparent interaction when the two were coincubated. The importance of understanding how opioid antagonists are absorbed by the nasal epithelium is magnified by the rise in overdose deaths attributed to long-lived synthetic opioids and the realization that better strategies are needed to treat opioid overdoses.