Plasma Pharmacokinetics Research Articles

Correction to: Unbound Plasma, Total Plasma and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Correction to: Unbound Plasma, Total Plasma and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Understanding the Blood-Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics.

This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood‐brain barrier (BBB) transport and intra‐CNS distribution in relation to CNS target site(s) exposure. To this end, we need to obtain and integrate quantitative and connected data on BBB using the Combinatory Mapping Approach that includes in vivo and ex vivo animal measurements, and the physiologically based comprehensive LEICNSPK3.0 mathematical model that can translate from animals to humans. For small molecules, slow diffusional BBB transport and active influx and efflux BBB transport determine the differences between plasma and CNS pharmacokinetics. Obviously, active efflux is important for limiting CNS drug delivery. Furthermore, liposomal formulations of small molecules may to a certain extent circumvent active influx and efflux at the BBB. Interestingly, for CNS pathologies, despite all reported disease associated BBB and CNS functional changes in animals and humans, integrative studies typically show a lack of changes on CNS drug delivery for the small molecules. In contrast, the understanding of the complex vesicle‐based BBB transport modes that are important for CNS delivery of large molecules is in progress, and their BBB transport seems to be significantly affected by CNS diseases. In conclusion, today, CNS drug delivery of small drugs can be well assessed and understood by integrative approaches, although there is still quite a long way to go to understand CNS drug delivery of large molecules.

A systematic evaluation of the cucurbit[7]uril pharmacokinetics and toxicity after a single dose and short-term repeated administration in mice.

Cucurbit[n]urils are macrocyclic compounds capable of forming host-guest complexes with different molecules. In this study, we focused on cucurbit[7]uril (CB[7]) safety and pharmacokinetics. We investigated CB[7] cytotocixity in human renal cells ACHN using the xCELLigence system. We also determined maximum tolerated doses (MTD) and no observed adverse effect levels (NOAEL) after intramuscular (i.m.), intraperitoneal (i.p.), and intragastric (i.g.) administration in mice using clinical observation, blood biochemistry, and histopathology. At NOAELs, we studied its pharmacokinetics in plasma and kidneys. Finally, we performed a 7day repeated-dose toxicity study at 50% of NOAEL after i.p. administration, assaying CB[7] concentration in plasma, brain, kidney, and liver; we also assessed the liver and kidney histopathology. In vitro, CB[7] did not show toxicity up to 0.94mg/mL. MTDs in vivo were set at 300, 350, and 600mg/kg, and NOAEL were established at 150, 100, and 300mg/kg after i.m., i.p., and i.g. administration, respectively. Parenteral administration produced tissue damage mainly to the kidney, while i.g. administration caused only minor liver damage. Parenteral CB[7] administration led to fast elimination from blood, accompanied with kidney accumulation; absorption from the gastrointestinal tract was minimal. Short repeated i.p. administration was well tolerated. After initial CB[7] accumulation in blood and kidney, the concentrations stabilised and decreased during the experiment. Approximately 3.6% of animals showed signs of nephrotoxicity. Although CB[7] appears to be a promising molecule, nephrotoxicity may be the most critical drawback of its parenteral use, because the kidney represents the main organ of its elimination.

Intra-articular injection of biologic anti-rheumatic drugs enhances local exposure to the joint-draining lymphatics

Recent reports have highlighted the role of the lymphatic system and its resident immune cells in the development of inflammatory arthritis. Directing therapeutics to the joint-draining lymphatics could improve access to lymphatic-resident pro-inflammatory immune cells, improve local treatment efficacy and enable the administration of lower drug doses to achieve the same or a better effect. Here, we assessed the delivery of disease modifying anti-rheumatic drugs (DMARDs) to the joint-draining lymphatics as a function of therapeutic size and route of administration (intravenous (IV), subcutaneous (SC) and intra-articular (IA) injection). The model drugs included the low molecular weight conventional DMARD methotrexate and the larger biologic DMARDs etanercept and rituximab. Plasma pharmacokinetics, thoracic lymph fluid concentrations and lymph node deposition of the DMARDS were assessed in male Sprague-Dawley rats after IV, IA or SC injection at or near the knee joint. Administration by IA injection resulted in rapid and higher absorption of all drugs into the systemic circulation, compared to SC administration. The large DMARDs etanercept and rituximab were preferentially transported from the IA and SC injection sites via the lymphatics, but a greater percentage of the absorbed dose was recovered in lymph after IA (49–58%) compared to SC administration (17–20%). Methotrexate was almost exclusively transported from the injection site via the blood after IA injection, consistent with its small size which presents minimal barriers to diffusion across the synovium into blood vessels. Importantly, IA but not SC administration resulted in biologic DMARD access to the knee joint-draining iliac lymph fluid and iliac lymph node that is dysfunctional in inflammatory knee arthritis. Overall, IA injection of biologic DMARDs may provide a simple strategy to improve lymph and lymph node access and thus the treatment of inflammatory arthritis.

A phase 1 first-in-human study of XL092 administered alone or in combination with immune checkpoint inhibitors (ICIs) in patients (pts) with inoperable locally advanced or metastatic solid tumors: Description of genitourinary (GU) expansion cohorts.

TPS401 Background: XL092 is a novel oral multi-targeted inhibitor of receptor tyrosine kinases MET, VEGFR2, and TAM kinases (AXL, MER), which are important in tumor growth, neovascularization, and immune modulation of the tumor microenvironment. XL092 as a single-agent and in combination with an anti-PD-1 antibody showed antitumor activity in xenograft tumor models (Hsu et al. 2020). This first-in-human study is evaluating safety, pharmacokinetics (PK), and preliminary antitumor activity of XL092 with or without (w/wo) ICIs in pts with advanced solid tumors. Presented here are the trial design and details of GU cohorts. Methods: In this phase 1, multicenter, open-label, dose-escalation and expansion study (NCT03845166), pts will receive escalating doses of XL092 w/wo atezolizumab (ATEZO) 1200 mg Q3W or avelumab (AVE) 800 mg Q2W. The dose-escalation stage is enrolling pts with inoperable locally advanced or metastatic solid tumors using a 3+3 (single-agent) or rolling 6 (combination) design; the primary objective is to determine maximum tolerated dose and/or recommended dose of XL092 for further evaluation when administered w/wo ICIs; secondary objective is to evaluate plasma PK of XL092 and its metabolites alone and in combination with ICIs. Primary objectives for the expansion stage are to evaluate preliminary efficacy of XL092 w/wo ICIs by estimating objective response rate (ORR) by investigator (Inv) per RECIST 1.1 and for specific cohorts by estimating the % of pts with PFS at 6 months by Inv per RECIST 1.1; secondary objective is safety of XL092 w/wo ICIs via monitoring nonserious and serious adverse events (AEs) including immune related AEs and AEs of special interest. For GU cohorts in expansion stage, single-agent XL092 will be tested in: (i) previously treated advanced clear cell (cc) renal cell carcinoma (RCC; progression on 1-3 prior systemic regimens w/wo a sarcomatoid component); (ii) previously treated advanced non-cc RCC (progression on 1-3 prior systemic regimens); (iii) metastatic castration resistant prostate cancer (mCRPC; prior treatment with ≥1 novel hormonal therapy and taxane-based chemotherapy, ≤4 prior systemic regimens). XL092 + ATEZO will be tested in non-cc RCC and mCRPC cohorts. Pts with advanced urothelial carcinoma will be enrolled in 3 cohorts: (i) pts with ongoing CR/PR/SD after 4-6 cycles of first-line chemotherapy (gemcitabine + cisplatin and/or gemcitabine + carboplatin) will receive XL092 + AVE; (ii) pts with progression on/after prior ICI therapy (≤2 prior systemic therapies) will be randomized 1:1 to XL092 + AVE or single-agent XL092; (iii) pts with progression on/after first-line platinum-based chemotherapy will receive XL092 + AVE. The study is currently enrolling pts. Clinical trial information: NCT03845166.

ABCB1 limits brain exposure of the KRASG12C inhibitor sotorasib, whereas ABCB1, CYP3A, and possibly OATP1a/1b restrict its oral availability

Sotorasib (Lumakras™) is the first FDA-approved KRASG12C inhibitor for treatment of patients with non-small cell lung cancer (NSCLC) carrying this mutation. Using genetically modified mouse models, we studied the influence of the efflux transporters ABCB1 and ABCG2, the OATP1a/1b uptake transporters, and the CYP3A drug-metabolizing enzyme complex on the plasma pharmacokinetics and tissue distribution of oral sotorasib. In vitro, sotorasib was a potent substrate for human ABCB1 and a modest substrate for mouse Abcg2, but not for human ABCG2. In vivo, the brain-to-plasma ratio of sotorasib (40 mg/kg) was highly increased in Abcb1a/1b-/- (5.9-fold) and Abcb1a/1b;Abcg2-/- (7.6-fold) compared to wild-type mice, but not in single Abcg2-/- mice. Upon coadministering elacridar, an ABCB1/ABCG2 inhibitor, sotorasib brain accumulation increased 7.5-fold, approaching the levels observed in Abcb1a/1b-deficient mice. No acute CNS toxicity emerged upon boosting of the sotorasib exposure. In Oatp1a/1b-deficient mice, we observed a 2-fold reduction in liver disposition compared to wild-type mice, although these uptake transporters had no noticeable impact on sotorasib plasma exposure. However, plasma exposure was limited by mouse Cyp3a and human CYP3A4, as the AUC0–4 h in Cyp3a-/- mice was increased by 2.5-fold compared to wild-type mice, and subsequently strongly decreased (by 3.9-fold) in Cyp3aXAV mice transgenically overexpressing human CYP3A4 in liver and intestine. Collectively, the oral availability of sotorasib was markedly limited by CYP3A and possibly also by ABCB1 and OATP1a/b, whereas its brain accumulation was strongly restricted by ABCB1. The obtained results may help to further optimize the safety and efficacy of sotorasib in clinical use.

Plasma pharmacokinetics, pulmonary disposition, and safety of subcutaneous gamithromycin in alpacas.

The study objective was to determine the disposition of gamithromycin in plasma, peripheral blood polymorphonuclear cells (PMNs), pulmonary epithelial lining fluid (PELF), and bronchoalveolar lavage (BAL) cells in alpacas. A single subcutaneous injection of gamithromycin (6.6mg/kg) was administered to six healthy adult alpacas. At various time points after administration, gamithromycin concentrations were analyzed via LC-MS/MS in plasma, PMNs, PELF, and BAL cells until Day 14 post-injection. Plasma gamithromycin concentrations were measured in all six alpacas; the remaining three body compartments were analyzed in four alpacas. Gamithromycin rapidly concentrated in blood PMNs, BAL cells, and PELF. Shorter Tmax , and lower Cmax, and AUC were observed in plasma than in the other three compartments. Cmax was highest in BAL cells (26001.80±12400.00ng/ml) and PMNs (2573.00±963.30ng/ml) compared to PELF (660.80±413.70ng/ml) and plasma (452.30±196.20ng/ml). Mean terminal half-lives were 72.60±14.10h in plasma, 56.60±10.60h in PELF, 62.80±85.30h in PMNs, and 93.60±124.80h in BAL cells. No injection site reactions occurred. One alpaca developed colic but no other adverse reactions were noted. Overall, gamithromycin was highly concentrated in white blood cells and pulmonary fluids/cells. Clinical utilization of gamithromycin in alpacas should be done with caution until further investigation of potential for colic.

P06 Pharmacokinetics and renal accumulation of VRP-034

BackgroundNephrotoxicity is a dose-limiting factor for polymyxin B (PMB), a last-line therapy for MDR Gram-negative bacterial infections. The majority of the filtered PMB undergoes extensive tubular reabsorption leading to significant accumulation of the drug in tubular cells, causing renal tubular damage. We have previously reported that VRP-034, a novel PMB formulation, attenuates this damage (Roy et al.1). The objective of this study was to characterize the pharmacokinetics (PK) and renal accumulation of VRP-034 versus marketed PMB.Materials and methodsA total of 19 Sprague-Dawley rats were used in the study. For PK evaluation, 10 rats were administered a single subcutaneous dose (6 mg/kg) of either VRP-034 or marketed PMB. Serial plasma samples were collected up to 24 h and assayed for major PMB components (PMB B1, B1-I, B2) using a validated LC-tandem MS method. PK parameters were calculated using noncompartmental analysis. For evaluating renal deposition, nine rats (n = 3 each group) were administered VRP-034 or marketed PMB at a dose of 6 mg/kg/8 h for 48 h or normal saline (control). After 48 h, rats were euthanized and kidneys were excised by making a midline incision, washed with saline, homogenized in 1:9 w/v 0.1 M phosphate buffer (pH 7.4) and the homogenate was used for determining PMB concentration. All values are expressed as mean ± SEM.ResultsThe plasma pharmacokinetic parameters for both VRP-034 and marketed PMB were found similar [AUC0–24: 54.3 ± 4.7 μg/mL·h versus 51.5 ± 1.6 μg/mL·h; Cmax: 4.73 ± 0.6 μg/mL versus 5.02 ± 0.5 μg/mL; T½: 5.95 ± 0.5 h versus 5.6 ± 0.3 h]. In the renal deposition study, a 40% reduction (P<0.05) in renal deposition of PMB was found in VRP-034 treated rat kidneys compared with marketed PMB group after 48 h of treatment.ConclusionsThe results highlight that while the plasma PK parameters remained unchanged, a marked reduction in PMB renal deposition was observed in VRP-034 group and likely explains the previous reports of attenuated PMB-induced kidney injury with VRP-034.

Effect of food on capsule and granule formulations of selumetinib.

Selumetinib is an oral, potent, and highly selective allosteric MEK1/2 inhibitor approved for the treatment of pediatric patients (aged ≥2 years) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. A granule formulation of selumetinib is under development to improve dosing precision for younger pediatric patients who may be unable to swallow capsules. This phase I crossover study investigated the effect of food on the pharmacokinetic (PK) properties of selumetinib capsule and granule formulations. Healthy male volunteers were randomized to receive selumetinib granules (25 mg) or capsules (50 mg [2 × 25 mg]) under fasted or fed conditions (a low‐fat meal). Plasma concentrations and PK parameters were determined less than or equal to 48 h postdose. Safety and tolerability were assessed. Across 24 volunteers, selumetinib was absorbed quickly, with a time to maximum concentration (Tmax) ranging from ~1–3 h. Geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (Cmax) in the fed versus fasted state were 0.61 (90% CI 0.51–0.72) and 0.40 (90% CI 0.33–0.48) for the granule and capsule formulations, respectively, whereas geometric mean ratios (90% CI) for area under the plasma drug concentration‐time curve in the fed versus fasted state were 0.97 (90% CI 0.91–1.02) and 0.62 (90% CI 0.55–0.70), respectively. Levels of less than 10% conversion to the N‐desmethyl selumetinib metabolite were observed. Selumetinib was well‐tolerated, with only a few adverse events of mild intensity reported. Selumetinib administration with a low‐fat meal resulted in lower Cmax and longer Tmax for both formulations versus fasted conditions. However, area under the curve for selumetinib granules was similar under fasted and fed conditions. Overall, these findings support further development of this formulation for pediatric patients.

Influence of tedizolid on the cytokine response to the endotoxin challenge in healthy volunteers: a cross-over trial.

Preclinical data suggested anti-inflammatory properties of tedizolid. To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid. In this cross-over trial, 14 male healthy volunteers underwent two treatment periods: (A) 200 mg of tedizolid phosphate once daily for 6 days (3 days orally and 3 days intravenously), followed by an intravenous bolus of 2 ng/kg body weight of LPS on the last treatment day; and (B) intravenous bolus of LPS (2 ng/kg body weight) without concomitant tedizolid treatment. Participants underwent first period A or B, separated by at least 6 weeks. Plasma was sampled to assess cytokines and the pharmacokinetics of tedizolid. Following the endotoxin challenge, the peak plasma concentration (median [IQR]; 280 [155-502] versus 287 [132-541] pg/mL; P = 0.875) and AUC0-24 (979 [676-1319] versus 1000 [647-1632] pg·h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC0-24 of TNF-α remained also unchanged with and without tedizolid (47 [31-61] versus 54 [27-69] pg/mL; P = 0.73 and 197 [163-268] versus 234 [146-280] pg·h/mL; P = 0.875, respectively). The total maximum concentration (mean ± SD; 2.94 ± 0.69 versus 2.96 ± 0.62 mg/L), total AUC0-24 (22.3 ± 3.8 versus 21.1 ± 3.6 mg·h/L) and protein binding (21.4% ± 1.7% versus 21.6% ± 1.9%) of tedizolid were similar with and without the endotoxin challenge. Tedizolid did not attenuate the LPS-induced cytokine response in healthy volunteers. Furthermore, endotoxaemia did not influence the plasma pharmacokinetics of tedizolid.

Pharmacokinetics and pharmacodynamics of repeat dosing of gabapentin in adult horses.

BackgroundThe repeated administration of high doses of gabapentin may provide better analgesia in horses than current clinical protocols.Hypothesis and ObjectivesAdministration of gabapentin at 40 and 120 mg/kg PO q 12 h for 14 days will not alter serum biochemistry findings or cause adverse effects. Our objectives were to evaluate the effect of gabapentin on serum biochemistry, physical examination, and plasma pharmacokinetics of gabapentin.AnimalsSix healthy adult mares.MethodsHorses received 40 and 120 mg/kg of gabapentin orally q 12 h for 14 days. Horses were examined and scored for ataxia and sedation daily. Serum biochemistry variables were analyzed before treatment and days 7 and 14 after gabapentin administration. Plasma disposition of gabapentin was evaluated after the first and last drug administration. Pharmacokinetic parameters were estimated using noncompartmental analysis.ResultsNo changes occurred in physiologic or biochemical variables. Median (range) maximal plasma gabapentin concentrations (μg/mL) after the last dose (day 15) were 7.6 (6.2‐11) and 22 (14‐33) for 40 mg/kg and 120 mg/kg doses respectively. Maximal concentration of gabapentin was reached within 1 hour after drug administration. Repeated administration of gabapentin resulted in a median (range) area under the curve (AUC0‐12 hours) last/first dose ratio of 1.5 (1.00‐2.63) and 2.92 (1.4‐3.8) for the 40 and 120 mg/kg regimens, respectively.Conclusion and Clinical ImportanceOur results suggest that horses tolerate gabapentin up to 120 mg/kg PO q 12 h for 14 days. The analgesic effect of the dosage regimens evaluated in our study warrants further research.

Pharmacokinetics and brain σ1 receptor occupancy of MR309, a selective σ1 receptor antagonist.

Preclinical studies of MR309, a selective sigma-1 receptor (σ1R) antagonist, support a potential role in treating neuropathic pain. We report 2 studies that provide insight into the pharmacokinetics (PK) and brain σ1R binding of MR309. Steady-state PK of MR309 (400 mg once daily and 200 mg twice-daily [BID] for 10 days; EudraCT 2015-001818-99 [PK study]) and the relationship between MR309 plasma exposure and brain σ1R occupancy (EudraCT 2017-000670-11 [positron emission tomography study]) were investigated in healthy volunteers. Positron emission tomography using the σ1R ligand [11 C]SA4503 was conducted at baseline, and 2 and 8 hours after a single dose of MR309 (200-800 mg). The relationship between brain σ1R occupancy and MR309 exposure was explored using data-driven model fitting. MR309 was well tolerated, brain σ1R occupancy ranged between 30.5 and 74.9% following single-dose MR309 (n =7). MR309 BID provided a plasma PK profile with less fluctuation than once daily dosing (n =16). MR309 200 mg BID yielded average steady state plasma concentrations between 2000 and 4000 ng/mL in the PK study, which corresponded to an estimated brain σ1R occupancy of 59-74%. MR309 200 mg BID dose was below the 75% σ1R occupancy threshold expected to elicit maximal antinociceptive effect as observed in neuropathic pain models. Further investigations of MR309 for neuropathic pain will require higher brain σ1R occupancy, and establish the optimal dose by elucidating the clinical impact of a broad range of brain σ1R occupancy across different neuropathic pain indications.

Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin.

Age is the most common risk factor for Alzheimer's disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Upon systemic injection of 125I-Aβ40, 125I-Aβ42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. The brain influx of 125I-Aβ40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

Effect of topical berberine in murine cutaneous leishmaniasis lesions.

ObjectivesMore effective topical treatments remain an unmet need for the localized forms of cutaneous leishmaniasis (CL). The aim of this study was to evaluate the efficacy and safety of a topical berberine cream in BALB/c mice infected with Leishmania major parasites.MethodsA cream containing 0.5% berberine-β-glycerophosphate salt and 2.5% menthol was prepared. Its physicochemical and stability properties were determined. The cream was evaluated for its capacity to reduce lesion size and parasitic load as well as to promote wound healing after twice-a-day administration for 35 days. Clinical biochemical profile was used for estimating off-target effects. In vitro time-to-kill curves in L. major-infected macrophages and skin and plasma pharmacokinetics were determined, aiming to establish pharmacokinetic/pharmacodynamic relationships.ResultsThe cream was stable at 40°C for 3 months and at 4°C for at least 8 months. It was able to halt lesion progression in all treated mice. At the end of treatment, parasite load in the skin was reduced by 99.9% (4 log) and genes involved in the wound healing process were up-regulated compared with untreated mice.The observed effects were higher than expected from in vitro time-to-kill kinetic and plasma berberine concentrations, which ranged between 0.07 and 0.22 μM.ConclusionsThe twice-a-day administration of a topical berberine cream was safe, able to stop parasite progression and improved the appearance of skin CL lesions. The relationship between drug plasma levels and in vivo effect was unclear.

Plasma Pharmacokinetics of Cannabidiol Following Oral Administration of Cannabidiol Oil to Dairy Calves.

Cannabidiol (CBD), the non-psychotropic component of cannabis, has drawn increased interest amongst some medical professionals for its potential therapeutic effects. Human and canine work has been done to describe CBD where it is already widely used, however, little is known about the effects of CBD in livestock species. The purpose of this descriptive study was to determine the pharmacokinetics (PK) of CBD in calves after a single oral exposure to CBD oil. Seven male Holstein calves received a single oral dose of 25 mg/mL CBD oil to achieve 5 mg/kg dose of CBD. Blood samples were collected for 48 (h) after dosing. The CBD geometric mean maximum concentration of 0.05 ug/mL was reached 7.5 h after administration. The geometric mean half-life was 23.02 h. Cannabidiol administered orally to cattle is slowly absorbed and has an extended elimination half-life compared to other species.

Pharmacokinetics and tissue distribution of tenofovir, emtricitabine and dolutegravir in mice.

Studies of antiretroviral drug (ARV) tissue distribution in preclinical models, such as mice, are key to understanding viral persistence. To determine the plasma and tissue pharmacokinetics and tissue distributions of tenofovir, emtricitabine and dolutegravir in mice. ARVs were simultaneously administered to two different strains, and their levels in plasma and tissue samples were determined by a validated LC-MS/MS method. A non-compartmental analysis was performed to estimate the main pharmacokinetic parameters. A tissue penetration factor (TPF) was calculated as the ratio of the concentration in the tissue concerned to that in plasma. ARV plasma pharmacokinetic parameters in both strains were similar to those estimated in the clinical context. Tissue concentrations were highest in the digestive tract, followed by the liver and kidneys, lymphatic system, pancreas, adipose tissue and lungs. Tissue concentrations were lowest in the brain. Triple therapy could not be considered effective in any of the tissues considered. The TPF values obtained showed that tenofovir diffused widely, especially in the digestive tract, liver and kidneys. Emtricitabine had a TPF above 100% in two-thirds of the tissues. Dolutegravir was poorly distributed to all tissues. Drug specificity was observed, with higher levels of exposure to tenofovir than to emtricitabine or dolutegravir. Tissue specificity was also observed, with strong penetration of the digestive tract and weak penetration of the brain. These data have important implications for future preclinical and clinical studies for developing new HIV therapies with the goal of an HIV cure.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Opicapone in Healthy Chinese and Caucasian Subjects: An Open-Label, Single-Center, Phase1 Study.

IntroductionThis study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses of opicapone (OPC) in healthy Chinese and Caucasian subjects.MethodsIn this open-label, single-center, phase 1 study, eligible Chinese subjects received one of three OPC doses (25, 50, or 100 mg), and Caucasian subjects received either 25 or 50 mg of OPC. All subjects were administered a single dose of OPC, whereas subjects in the 50-mg OPC group continued to receive once-daily doses of 50 mg OPC for 10 days. The primary endpoint was to evaluate and compare the plasma concentrations and PK parameters of OPC and its main metabolite, and erythrocyte-soluble catechol-O-methyltransferase (S-COMT) activity in Chinese subjects with that of Caucasian subjects. The secondary endpoint was to evaluate the safety of OPC in Chinese subjects. The estimated results for geometric mean ratios (GMRs) were evaluated with the standard bioequivalence (BE) limits between 80% and 125% to evaluate the ethnic differences. All statistical analyses were performed using SAS version 9.4.ResultsIn total, 70 subjects (45 Chinese, 25 Caucasian) were enrolled; the majority of them were male (85.7%). The plasma exposure of both OPC and BIA 9-1103 increased in an approximately dose-proportional manner in both populations. Maximum S-COMT inhibition ranged from 79% to 95% after a single dose and was about 94% after a 10-day once-daily regimen in both populations. The point estimates of GMRs (Chinese/Caucasian) and 90% CI, except Cmax in 25-mg and 50-mg OPC groups, for PK and PD parameters were within 80% to 125%. Furthermore, no new risks or safety concerns associated with OPC were identified, indicating a tolerable safety profile in healthy Chinese subjects.ConclusionEthnicity had no significant impact on PK and PD parameters after single or multiple doses of OPC, and OPC was safe and tolerable in healthy Chinese subjects.Trial RegistrationChiCTR number, CTR20192230.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00314-8.

Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin.

Background and ObjectiveIn microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid.MethodsHealthy subjects received a single intravenous bolus injection of a microdose of [14C]ciprofloxacin (1.1 µg, 7 kBq) with (cohort A, n = 9) or without (cohort B, n = 9) a prior intravenous infusion of a therapeutic dose of unlabeled ciprofloxacin (400 mg). Microdialysis and bronchoalveolar lavage were applied for determination of subcutaneous and intrapulmonary drug concentrations. Microdose [14C]ciprofloxacin was quantified by accelerator mass spectrometry and therapeutic-dose ciprofloxacin by liquid chromatography–tandem mass spectrometry.ResultsThe pharmacokinetics of therapeutic-dose ciprofloxacin (cohort A) in plasma, subcutaneous tissue, and epithelial lining fluid was in accordance with previous data. In plasma and subcutaneous tissue, the dose-adjusted area under the concentration–time curve of microdose ciprofloxacin was similar in cohorts A and B and within an 0.8-fold to 1.1-fold range of the area under the concentration–time curve of therapeutic-dose ciprofloxacin. Penetration of microdose ciprofloxacin into subcutaneous tissue was similar in cohorts A and B and comparable to that of therapeutic-dose ciprofloxacin with subcutaneous tissue-to-plasma area under the concentration–time curve ratios of 0.44, 0.44, and 0.38, respectively. Penetration of microdose ciprofloxacin into epithelial lining fluid was highly variable and failed to predict the epithelial lining fluid penetration of therapeutic-dose ciprofloxacin.ConclusionsOur study confirms the feasibility of microdosing for pharmacokinetic measurements in plasma and subcutaneous tissue. Microdosing combined with microdialysis is a potentially useful tool in clinical antimicrobial drug development, but its applicability for the assessment of pulmonary pharmacokinetics with bronchoalveolar lavage requires further studies.Clinical Trial RegistrationClinicalTrials.gov NCT03177720 (registered 6 June, 2017).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01091-1.

Pharmacokinetics in plasma and alveolar regions of a healthy calf intramuscularly administered a single dose of orbifloxacin.

This study analyzed the pharmacokinetics of orbifloxacin (OBFX) in plasma, and its migration and retention in epithelial lining fluid (ELF) and alveolar cells within the bronchoalveolar lavage fluid (BALF). Four healthy calves received a single dose of OBFX (5.0 mg/kg) intramuscularly. Post-administration OBFX dynamics were in accordance with a non-compartment model, including the absorption phase. The maximum concentration (Cmax) of plasma OBFX was 2.2 ± 0.1 μg/ml at 2.3 ± 0.5 hr post administration and gradually decreased to 0.3 ± 0.2 μg/ml at 24 hr following administration. The Cmax of ELF OBFX was 9.3 ± 0.4 μg/ml at 3.0 ± 2.0 hr post administration and gradually decreased to 1.2 ± 0.1 μg/ml at 24 hr following administration. The Cmax of alveolar cells OBFX was 9.3 ± 2.9 μg/ml at 4.0 hr post administration and gradually decreased to 1.1 ± 0.2 μg/ml at 24 hr following administration. The half-life of OBFX in plasma, ELF, and alveolar cells were 6.9 ± 2.2, 7.0 ± 0.6, and 7.8 ± 1.6 hr, respectively. The Cmax and the area under the concentration-time curve for 0–24 hr with OBFX were significantly higher in ELF and alveolar cells than in plasma (P<0.05). These results suggest that OBFX is distributed and retained at high concentrations in ELF and alveolar cells at 24 hr following administration. Hence, a single intramuscular dose of OBFX (5.0 mg/kg) may be an effective therapeutic agent against pneumonia.

Benzo[a]pyrene (BaP) metabolites predominant in human plasma following escalating oral micro-dosing with [14C]-BaP.

Benzo[a]pyrene (BaP) is formed by incomplete combustion of organic materials (petroleum, coal, tobacco, etc.). BaP is designated by the International Agency for Research on Cancer as a group 1 known human carcinogen; a classification supported by numerous studies in preclinical models and epidemiology studies of exposed populations. Risk assessment relies on toxicokinetic and cancer studies in rodents at doses 5-6 orders of magnitude greater than average human uptake. Using a dose-response design at environmentally relevant concentrations, this study follows uptake, metabolism, and elimination of [14C]-BaP in human plasma by employing UPLC - accelerator mass spectrometry (UPLC-AMS). Volunteers were administered 25, 50, 100, and 250ng (2.7-27 nCi) of [14C]-BaP (with interceding minimum 3-week washout periods) with quantification of parent [14C]-BaP and metabolites in plasma measured over 48h. [14C]-BaP median Tmax was 30min with Cmax and area under the curve (AUC) approximating dose-dependency. Marked inter-individual variability in plasma pharmacokinetics following a 250ng dose was seen with 7 volunteers as measured by the Cmax (8.99±7.08ng×mL-1) and AUC0-48hr (68.6±64.0fg×hr-1×mL-1). Approximately 3-6% of the [14C] recovered (AUC0-48 hr) was parent compound, demonstrating extensive metabolism following oral dosing. Metabolite profiles showed that, even at the earliest time-point (30min), a substantial percentage of [14C] in plasma was polar BaP metabolites. The best fit modeling approach identified non-compartmental apparent volume of distribution of BaP as significantly increasing as a function of dose (p=0.004). Bay region tetrols and dihydrodiols predominated, suggesting not only was there extensive first pass metabolism but also potentially bioactivation. AMS enables the study of environmental carcinogens in humans with de minimus risk, allowing for important testing and validation of physiologically based pharmacokinetic models derived from animal data, risk assessment, and the interpretation of data from high-risk occupationally exposed populations.