Simultaneous determination of ginkgolide A, B, C, bilobalide and rutin in rat plasma by LC-MS/MS and its application to a pharmacokinetic study

A reliable LC-MS/MS method for the determination of five bioactive constituents (bilobalide, BLL; ginkgolide A, GLA; ginkgolide B, GLB; ginkgolide C, GLC; rutin) of Ginkgo biloba leaf extracts (GBE) in rat plasma was established, fully validated and applied to an intragastric pharmacokinetic study of a preparation of GBE in rat. Samples were extracted with ethyl acetate. C18 column was selected as analytical column in this method. Mobile phase was water with 0.01% formic acid and acetonitrile. Quantification was performed in negative multiple-reaction monitoring mode. Matrix instability of terpene lactones was noticed and hydrochloric acid was used as a stabilizer. This method showed good precision and accuracy, recovery was reproducible and matrix effect was negligible. Among four terpene lactones, BLL had the highest exposure and the shortest terminal half-life, GLA and GLB had lower exposure and longer terminal half-life, the exposure of GLC was lowest and its terminal half-life was the maximum, and all of them showed rapid absorption. This study provides a reference for determination of terpene lactones and flavonol glycoside prototypes in GBE and offers pharmacokinetic data of flavonol glycoside prototype in GBE.

Dalbavancin

Dalbavancin is a long-acting antimicrobial agent with an excellent in vitro activity against Gram-positive pathogens, including staphylococcal biofilms. The unusually long terminal half-life ranging from 149 to 250 hours in human subjects, allows a weekly dose. Currently is indicated in acute bacterial skin and skin structure infections (ABSSSIs), but in real-life clinical practice it has already been used successfully and safely in other infections, especially as consolidation therapy.

Pharmacokinetic-Pharmacodynamic Profile, Bioavailability, and Withdrawal Time of Tylosin Tartrate Following a Single Intramuscular Administration in Olive Flounder (Paralichthys olivaceus)

The objective of this study was to demonstrate the pharmacokinetic–pharmacodynamic profile, bioavailability, and withdrawal time of tylosin tartrate (TT) administered to olive flounder via intramuscular (IM, 10 or 20 mg/kg, n = 240) and intravascular (IV, 10 mg/kg, n = 90) injections. Serum concentrations of tylosin were determined using a validated liquid chromatography-tandem mass spectrometry method. According to the non-compartmental analysis, the bioavailability of TT was 87%. After the IV injection, the terminal half-life, total body clearance, volume of distribution, and mean residence time of TT were 21.07 h, 0.07 L/kg/h, 2.15 L/kg, and 16.39 h, respectively. Rapid absorption (Tmax 0.25 h), prolonged action (terminal half-life, 33.96 and 26.04 h; MRT, 43.66 and 33.09 h), and linear dose–response relationship (AUC0-inf, 123.55 and 246.05 µg/mL*h) were monitored following 10 and 20 mg/kg IM injection. The withdrawal time of TT from muscle (water temperature, 22 °C) was 9.84 days, rounded up to 10 days (220 degree days). Large Cmax/MIC90, AUC0-inf/MIC90, and T > MIC90 values were obtained for Streptococcus isolates and these PK/PD indices satisfied the criteria required for efficacy evaluation. This study lays a foundation for the optimal use of TT and provides valuable information for establishing therapeutic regimens.

Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants

Background Perinatal HIV-1 continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs). Methods Extended half-life bNAb, VRC01LS, was administered subcutaneously (SC) at 80 mg/dose after birth to HIV-1-exposed, non-breastfed (Cohort 1, n=10) and breastfed (Cohort 2, n=11) infants. Cohort 2 received a second dose (100mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort. Results Local reactions (all Grade <2) occurred in 67% and 20% after Dose 1 and Dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administrated SC achieved a mean +SD plasma level of 222.3 + 71.6 mcg/mL by 24 hours and 44.0 + 11.6 mcg/mL at week 12, prior to Dose 2. The pre-established target of > 50 mcg/mL was attained in 95% and 32% at week 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after one dose was significantly greater (p=<0.002) than after a VRC01 dose (20mg/kg). No infants acquired HIV-1. Conclusions VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with ARVs to prevent infant HIV-1 transmission.

Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd2Spm) in Mice

Palladium-based compounds are regarded as potential analogs to platinum anticancer drugs with improved properties. The present study assessed the pharmacokinetics and biodistribution of a dinuclear palladium(II)-spermine chelate (Pd2Spm), which has previously been shown to possess promising in vitro activity against several therapy-resistant cancers. Using inductively coupled plasma-mass spectrometry, the kinetic profiles of palladium/platinum in serum, serum ultrafiltrate and tissues (kidney, liver, brain, heart, lungs, ovaries, adipose tissue and mammary glands) were studied in healthy female Balb/c mice after a single intraperitoneal bolus injection of Pd2Spm (3 mg/kg bw) or cisplatin (3.5 mg/kg bw) between 0.5 and 48 h post-injection. Palladium in serum exhibited biphasic kinetics with a terminal half-life of 20.7 h, while the free palladium in serum ultrafiltrate showed a higher terminal half-life than platinum (35.5 versus 31.5 h). Palladium was distributed throughout most of the tissues except for the brain, with the highest values in the kidney, followed by the liver, lungs, ovaries, adipose tissue and mammary glands. The in vitro cellular accumulation was also evaluated in breast cancer cells, evidencing a passive diffusion as a mechanism of Pd2Spm’s cellular entry. This study reports, for the first time, the favorable pharmacokinetics and biodistribution of Pd2Spm, which may become a promising pharmacological agent for cancer treatment.

Pharmacokinetics and Immunological Effects of Romidepsin in Rhesus Macaques

HIV/SIV persistence in latent reservoirs requires lifelong antiretroviral treatment and calls for effective cure strategies. Romidepsin (RMD), a histone deacetylase inhibitor, was reported to reactivate HIV/SIV from reservoirs in virus-suppressed individuals. We characterized in detail the pharmacokinetics and safety profile of RMD in three SIV-naïve rhesus macaques which received two rounds of treatment. In plasma, RMD mean terminal half-life was 15.3 h. In comparison, RMD mean terminal half-life was much longer in tissues: 110 h in the lymph nodes (LNs) and 28 h in gastrointestinal tract. RMD administration was accompanied by transient liver and systemic toxicity. Isoflurane anesthesia induced near-immediate transient lymphopenia, which was further exacerbated and extended with the extensive immune modifications by RMD. The effect of RMD on circulating immune cells was complex: (i) slight increase in lymphocyte death rates; (ii) transient, robust increase in neutrophils; (iii) massive downregulation of lymphocyte surface markers; (iv) important migration of CD3+ T cells to the gut and LNs; and (v) hindrance to CD8+ T cell functionality, yet without reaching significance. Our results show that, in contrast to transient plasma concentrations, RMD has a long-term presence in tissues, with multiple immunomodulatory effects and minimal to moderate kidney, liver, and lymphocyte toxicities. As such, we concluded that RMD can be used for “shock and kill” approaches, preferentially in combination with other latency reversal agents or cytotoxic T lymphocyte boosting strategies with consideration taken for adverse effects.

Accidental apixaban intoxication in a 23-month-old child: a case report

Background Direct oral anticoagulants, such as apixaban, are increasingly used in everyday practice in order to treat or prevent thromboembolic diseases. To date, there is no available data about apixaban pharmacokinetics in children, and no intoxication has previously been described. Case presentation A 23-month-old boy, with no medical history, was admitted to the emergency department 2 h after accidentally ingesting 40 mg apixaban and 0.75 mg digoxin. No adverse event was observed. Digoxin trough level was within therapeutic values. Apixaban blood concentration increased up to 1712 μg/L at H + 6 (1000–2750 μg/L using 2–5 mg/kg of apixaban in adults). The terminal half-life was 8.2 h (6–15 h in adults). The rapid elimination may explain the absence of bleeding despite high concentrations. Conclusions Despite an important intake of apixaban and a real disturbance in routine coagulation assays, no clinical sign of bleeding was observed, perhaps due to wide therapeutic range of apixaban. It may also be explained by its rapid elimination. Considering the high Cmax and a possible enteroenteric recycling, the use of activated charcoal should be considered in such situations in order to prevent eventual bleeding.

Terminal Half-Life of Factor VIII/IX According to Age and Blood Group Based on 8550 Assessments

Introduction: Extended half-life concentrates were recently introduced and limited data have shown extended terminal half-life (THL). However, real-life data on pharmacokinetics in large cohorts of patients with haemophilia (PWH) and information on the effects of age, body composition and blood group (THL) are lacking. Aim: to assess THL for standard half-life (SHL) and extended half-life (EHL) concentrates according to age and blood group. Methods: Data on THL, age and blood group were extracted from the WAPPS (Web-Accessible Population Pharmacokinetics Service; www.wapps-hemo.org) database. WAPPS provides an on-line service of individual pharmacokinetic (PK) calculations for clinicians, based on concentrate-specific population pharmacokinetic models. Informed consent was waived by the ethical committee. THL according to age and blood group was assessed by multivariable linear modelling. Results: Infusion data (n=8550) was collected from 4832 (2222 children, 2610 adults) patients with severe haemophilia (89% haemophilia A; 34% treated with EHL concentrates, 9.7% with history of inhibitors, median age: 20 (range: 1 month - 85 years)). Details on infusions, calculated THL and results from regression models are shown in Table 1. For factor VIII, median THL was longer in EHL at 15.1 hours (interquartile range (IQR): 12.0-19.0) vs. 11.1 hours (8.8-14.2) in SHL-FVIII. Linear models identified age, type of concentrate and blood group as independent predictors of THL in FVIII. THL increased with age by 1 hour/10 years, and THL was 2.2 hours longer in patients with blood group non-O, independent of concentrate type. For FIX, median THL was considerably longer in EHL at median 106.9 (81.1-134.2) vs. 36.5 (31.2-42.6) hours in SHL. Age was only a significant predictor of THL in children using EHL-FIX concentrates: THL increased by 2,5 hours/year until adulthood for EHL concentrates (e.g.: from 77 hrs at age 4 to 112 hrs at age 18), whereas THL was stable across all ages for SHL-FIX. THL was stable across blood groups for all FIX concentrates. In PWH with a positive inhibitor history, THL was decreased by 1,3 hours for FVIII and 22 hours for FIX. Discussion: This study was the largest study describing THL according to concentrate type and patient characteristics so far. At group level, a significant extension of THL was confirmed for both FVIII-EHL and FIX-EHL. THL was associated with age and blood group for all FVIII concentrates. In contrast, THL for FIX concentrates, was only associated with age in children using EHL-FIX. THL was significantly reduced in patients with a history of inhibitors. The results support the need for individual assessment of THL, especially for patients with haemophilia A and children treated with EHL-FIX. This was a group-based study. Within the age of personalized medicine, individualized PK assessments seem more appropriate. Our next project will be to analyse the effects of switching from SHL to EHL in individual patients. Disclosures Versloot: Bayer: Research Funding. Germini:Bayer: Research Funding; Roche: Research Funding; Takeda: Research Funding; NovoNordisk: Research Funding. Iorio:CSL: Research Funding; BioMarin: Research Funding; Bayer: Research Funding; Uniqure: Research Funding; Takeda: Research Funding; Spark: Research Funding; Sanofi: Research Funding; Roche: Research Funding; Pfizer: Research Funding; Octapharma: Research Funding; NovoNordisk: Research Funding; Grifols: Research Funding; Freeline: Research Funding. Fischer:Bayer, Biogen, Pfizer, Baxter/Shire, and Novo Nordisk: Research Funding; Bayer, Baxter, Biogen, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, and Sobi: Consultancy; Bayer, Baxter/Shire, SOBI/Biogen, CSL Behring, Octapharma, Pfizer, NovoNordisk: Research Funding.

Simultaneous quantification of five bioactive 16-deoxybarringtogenol C triterpenoid saponins in rat plasma by HPLC-MS: Application to a pharmacokinetic study after oral administration of Xanthoceras sorbifolia Bunge husks extract

In this study, a simple and rapid liquid chromatography-mass spectrometry method was developed to simultaneously determinate five 16-deoxybarringtogenol C triterpenoid saponins with the potential of neuroprotection in rat plasma following the oral administration of the Xanthoceras sorbifolia Bunge husks extract. With digoxin as the internal standard, the plasma samples were pre-treated by ethyl acetate-isopropanol (1:1, v/v). The chromatographic separation of the five analytes was performed using a Phenomenex C18 column (250 mm × 4.6 mm, 5.0 mm) with a mobile phase of 0.05% formic acid (A)-acetonitrile (B). The mass spectrometric detection was carried out in the selected ion mode in positive ionization. The extraction recoveries of the five analytes were all over 71.28%. The established method was fully validated in line with the ICH and Food and Drug Administration (FDA) guidelines and successfully applied to the pharmacokinetic study on the five analytes in rat plasma. The terminal half-life (t1/2) of the five analytes was 2.92 ± 0.57, 5.52 ± 1.75, 2.48 ± 0.62, 2.95 ± 0.94, and 2.34 ± 0.81, respectively. This study was purposed to investigate the oral pharmacokinetic parameters and gain an in-depth insight into the reasonable preclinical use of the husks extract derived from X. sorbifolia Bunge.