The effect of route of administration on the enantioselective pharmacokinetics of ketamine and norketamine in rats

Background: Ketamine has been shown to produce a rapid and potent antidepressant response in patients with treatment-resistant depression. Currently ketamine is most commonly administered as a 40-minute intravenous infusion, though it is unknown whether this is the optimal route of administration. Aims: To determine the plasma concentration time course of the R- and S-enantiomers of ketamine and norketamine following administration of ketamine by four different routes of administration. Methods: Plasma from conscious non-anaesthetised rats was collected following administration of ketamine by either subcutaneous (SC), intramuscular (IM), intravenous infusion (IVI) or intravenous bolus (IVB) routes of administration. Concentrations of the enantiomers of ketamine and norketamine were determined by LC/MS. Results: Administration by the SC, IM and IVI routes produced an overall similar drug exposure. In contrast, administration by the IVB route produced approximately 15-fold higher peak plasma concentrations for the enantiomers of ketamine and an approximately four-fold lower AUC for the enantiomers of norketamine. Conclusions: Route of administration can significantly influence ketamine and norketamine exposures. These differences may influence safety and tolerability, and potentially drug efficacy in humans. This knowledge adds to current research into the optimisation of the use of ketamine for the treatment of depression.

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Abstract 14004: Pharmacodynamic Profiles of Ticagrelor in Patients With ST-Elevation Myocardial Infarction: A Prospective Randomized Comparison of Escalating Loading Dose Regimens

Circulation ◽

10.1161/circ.130.suppl_2.14004 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Francesco Franchi ◽

Fabiana Rollini ◽

Jung Rae Cho ◽

Mona Bhatti ◽

Christopher DeGroat ◽

...

Keyword(s):

Myocardial Infarction ◽

Time Course ◽

Peak Plasma ◽

Platelet Reactivity ◽

Randomized Study ◽

Plasma Concentrations ◽

St Elevation Myocardial Infarction ◽

Reactivity Index ◽

Loading Dose ◽

St Elevation

Background: Pharmacodynamic (PD) studies have shown that in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI), ticagrelor is associated with suboptimal platelet inhibition and elevated rates of high on-treatment platelet reactivity (HPR) in the early hours after loading dose (LD) administration. Impaired absorption affecting drug pharmacokinetics (PK) has been hypothesized as a contributing factor suggesting increasing LD regimens to improve PK/PD profiles. To date there are no randomized studies which have investigated the PK/PD effects of escalating ticagrelor LD regimens in patients undergoing PPCI. Methods: In this prospective, randomized study, STEMI patients undergoing PPCI (n=52) were randomized 1:1:1 to receive 180mg, 270mg or 360mg LD of ticagrelor. PK and PD analysis were performed before and at 6 time points after LD. PD assessments included P2Y 12 reaction units (PRU) measured by VerifyNow P2Y12 and platelet reactivity index (PRI) measured by VASP. PK assessments included plasma concentrations of ticagrelor and its metabolite AR-C124910XX. Results: At baseline there were no differences in platelet reactivity between groups. At 2 hrs (primary endpoint), there were no differences in PRU between groups (p=0.54). There were no differences in PRU between groups during the overall study time course (p=0.17; Figure). Accordingly, HPR (PRU>208) at 2 hrs was observed in 30% of patients and was not reduced by escalating ticagrelor LD regimens. Consistent PD findings were observed with VASP-PRI. PK data tracked PD results, with a non-dose related delay in peak plasma concentrations of both ticagrelor and AR-C124910XX, particularly in HPR patients. Conclusions: In STEMI patients undergoing PPCI, increasing the LD regimen of ticagrelor did not translate into more prompt or potent P2Y 12 inhibition, which is attributed to impaired absorption in the early hours after drug administration.

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Plasma and tissue pharmacokinetics of fosfomycin in morbidly obese and non-obese surgical patients: a controlled clinical trial

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz203 ◽

2019 ◽

Vol 74 (8) ◽

pp. 2335-2340 ◽

Cited By ~ 3

Author(s):

Christoph Dorn ◽

David Petroff ◽

Nancy Neumann ◽

Alexander Kratzer ◽

Nahed El-Najjar ◽

...

Keyword(s):

Drug Exposure ◽

Peak Plasma ◽

Subcutaneous Tissue ◽

Plasma Concentrations ◽

Surgical Patients ◽

Pharmacokinetic Analysis ◽

Controlled Clinical Trial ◽

Morbidly Obese ◽

Obese Patients ◽

Tissue Pharmacokinetics

Abstract Objectives To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. Methods Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. Results Thirteen obese patients (BMI 38–50 kg/m2) and 14 non-obese patients (BMI 0–29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047). Conclusions Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.

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An open-label phase I dose escalation study of KRN951, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 1 in a 4 week on, 2 week off schedule in patients with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2034 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2034-2034 ◽

Cited By ~ 11

Author(s):

F. A. Eskens ◽

A. Planting ◽

L. Van Doorn ◽

T. Isoe ◽

K. Hayashi ◽

...

Keyword(s):

Growth Factor ◽

Drug Exposure ◽

Kinase Inhibitor ◽

Peak Plasma ◽

Plasma Concentrations ◽

Growth Factor Receptor ◽

Pharmacokinetic Analysis ◽

Dose Escalation Study ◽

Once Daily ◽

Grade 3

2034 Background: KRN951 inhibits VEGF induced phosphorylation of VEGF receptors (VEGFR)2 and 1 (IC50 of 0.16 and 0.21 nM) and phosphorylation of c-Kit and Platelet Derived Growth Factor Receptor (PDGFR), (IC50 of 1.63 and 1.72 nM). Methods: The principal objectives of this study were (1) to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of KRN951 administered once daily (OD) for 28 days followed by 14 days off treatment, (2) to characterize safety and tolerability, (3) to characterize single and multiple dose pharmacokinetics, (4) to explore inhibitory effects on tumor blood flow, and (5) to look for evidence of antitumor activity. Results: 10 male and 5 female patients, median age 57 yrs (28–72) have been enrolled at dose levels of 1 mg (n=6), 2 mg (n=8), and 1.5 mg (n=1). The total number of courses given is 63 (1–15 per patient) At 2 mg DLT consisting of grade 3 asymptomatic proteinuria, grade 3 ataxia and grade 4 intracranial hemorrhage was seen in three patients. In the next-lower dose level of 1 mg one DLT (grade 3 fatigue) was seen. An intermediate dose of 1.5 mg is currently studied. Hypertension occurred in 14/15 patients but could be medically controlled. Pharmacokinetic analysis revealed dose dependent drug exposure and peak plasma concentrations. Plasma levels of sVEGFR2 decreased following exposure to KRN951. Exploratory analysis by means of Dynamic Contrast Enhanced MRI analysis indicated a decrease in tumorperfusion in selected patients. One confirmed partial response lasting more than 80 weeks in a patient with renal cell carcinoma was seen, and stable disease lasting more than 2 courses of treatment was seen in 6 patients. Conclusion: Once daily KRN951 can be administered safely when given for 28 days followed by 14 days off treatment. The recommended phase II dosing is currently being defined. No significant financial relationships to disclose.

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Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14690 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14690-e14690

Author(s):

Sihem Ait-Oudhia ◽

Donald E. Mager ◽

Garin Tomaszewski ◽

Adrienne E. Groman ◽

Patricia D. Zagst ◽

...

Keyword(s):

Mathematical Modeling ◽

Hepatocellular Carcinoma ◽

Tumor Growth ◽

Tumor Progression ◽

Time Course ◽

Drug Exposure ◽

Plasma Concentrations ◽

Target Range ◽

Tumor Growth Inhibition ◽

Time To Tumor Progression

e14690 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with 250,000 new annual cases in the US. Sunitinib (SU), an oral tyrosine kinase inhibitor, inhibits tumor cell proliferation, selectively binds to the angiogenesis biomarker (VEGFR2), and is metabolized to an equipotent metabolite (SU12662). The objective of this study is to utilize mathematical modeling to bridge drug exposure and VEGFR2 dynamics to tumor growth inhibition (TGI) and time-to-tumor progression (TTP). Methods: Plasma concentrations of SU, SU12662, and VEGFR2, and tumor growth and TTP measurements were obtained from a phase-II study in 16 patients with unresectable HCC. SU was administered at 37.5 mg daily 7-days prior to chemoembolization, then on days 15-35. A MAP Bayesian approach was utilized to model SU and SU12662 pharmacokinetics (PK), both captured with a two-compartment model including linear clearances. Inhibition of VEGFR2 production was mediated by predicted active unbound concentrations (ACub) of SU and SU12662. VEGFR2 concentrations were the driver for TGI. The TTP probability was modeled with exponential hazard function dependent on a time varying covariate -the difference in VEGFR2 concentration from its baseline (ΔVEGFR2). Results: Drug and metabolite clearances (CLd, CLm) were estimated at 30.3 (19, %RSE) and 19.7L/h (14). Their volumes of distribution (Vd, Vm) were 1,780 (39) and 1840L (25). SU exposure was within target range for VEGFR2 inhibition. VEGFR2 half-life in plasma was calculated at 4h. The slope (α) for ACub effect on VEGFR2 production was 0.77(µg/mL)-1 (14). The ΔVEGFR2 effect on TGI was assumed maximal, whereas its potency (ΔIC50) was estimated at 1.83x10-2µg/mL (41). The between-subjects variabilities were 37.4, 51, 44.7, 64.8, 21, and 36% for CLd, CLm, Vd, Vm, α, and ΔIC50. The median observed tumor size baseline was 91 mm3. The simulated mean TTP was 7 months. Conclusions: The time-course of SU, SU12662, and VEGFR2 were captured well with final PK/pharmacodynamic models. VEGFR2 profiles successfully linked drug exposure to TGI and TTP. This model may serve as a general platform for the dynamics of anti-angiogenic drugs.

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Performance of Murine Soluble Thrombomodulin (rmsTM) in a Murine Model of Endotoxin-Induced Sepsis.

Blood ◽

10.1182/blood.v108.11.3933.3933 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3933-3933

Author(s):

David E. Joyce ◽

Haifeng Xu ◽

Sumeet Mathur ◽

Francis J. Castellino

Keyword(s):

Protein C ◽

Time Course ◽

Peak Plasma ◽

Plasma Concentrations ◽

Initial Time ◽

Survival Study ◽

Sepsis Model ◽

Survival Difference

Abstract The endothelial surface protein thrombomodulin (TM) generates activated protein C (aPC) that protects from sepsis-related DIC, vascular inflammation, and apoptosis. The purpose of this study is to evaluate a novel recombinant mouse soluble TM (Eli Lilly, Indianapolis, IN) in a murine lethal endotoxin (LPS) sepsis model to determine both kinetic and survival endpoints. A dose effective in rodent reperfusion studies was employed in this sepsis model (D. Berg, Eli Lilly). C57BL6 mice were injected concomitantly with rmsTM 5 mg/kg (s.c.) and LPS 14 ug/g (i.p.) at time zero. Plasma concentrations were determined from citrated plasma at 3, 12, 24, and 48 hr, and plasma rmsTM concentrations were determined by ELISA. In vitro determinations of mouse aPC amidolytic activity and rmsTM dependent fibrinogen clotting time assays utilized rmsTM, murine thrombin, fibrinogen, and Protein C (Enzyme Research Labs). The in-vivo time-dependent mouse plasma kinetic studies confirmed plasma concentrations comparable to that achieved in human sTM antithrombotic studies. Thus, an rmsTM dose of 5 mg/kg was chosen for the 7-day LPS survival study (20% survival model). Twenty age-and weight-matched male C57BL6 mice, age 8–14 weeks, were treated with LPS 14 ug/g or LPS and rmsTM, 5 mg/kg, s.c. Survival curves were analyzed by Wilcoxon rank sum test (power 80%, alpha 2.5, p<0.05). An initial time course after rmsTM s.c. injection yielded a peak plasma rmsTM level at 3 hr (5,000 ng/mL) which persisted up to 48 hr (2,000 ng/mL). In vitro activation of aPC was saturating (2,000 ng/mL aPC with <20 ng/mL rmsTM). Prolongation of the thrombin clot time occurred at approximately 10 ug/ml of rmsTM. The LPS survival study in C57BL6 administered LPS (14 ug/g, i.p.) or LPS and rmsTM 5mg/kg s.c. demonstrated no survival difference (P=0.63). In vitro evaluation of aPC generation by rmsTM yielded ample amounts of aPC. Similarly, reduction of thrombin activity by rmsTM occurred at higher rmsTM concentrations. Thus, the lack of survival difference seen between endotoxemic mice treated with saline or adjunctive rmsTM in this model may be from the lack of thrombin inhibition, the lack of persistent (rmsTM:Thrombin) PC activation, or by more efficient clearance of aPC. Species specificity of TM is less likely a contributing factor. Further elucidation of the murine thrombin/thrombomodulin regulatory mechanism in vivo may be necessary to help explain our unexpected sTM survival results.

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Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review

Medicina ◽

10.3390/medicina56060309 ◽

2020 ◽

Vol 56 (6) ◽

pp. 309 ◽

Cited By ~ 2

Author(s):

Lourdes Poyatos ◽

Ana Pilar Pérez-Acevedo ◽

Esther Papaseit ◽

Clara Pérez-Mañá ◽

Soraya Martin ◽

...

Keyword(s):

Systematic Review ◽

Oral Administration ◽

Peak Plasma ◽

Plasma Concentrations ◽

Limited Information ◽

Routes Of Administration ◽

Baked Goods ◽

Oral Formulations ◽

Medicinal Use ◽

Pubmed Database

Background and objective: Changes in cannabis legalization regimes in several countries have influenced the diversification of cannabis use. There is an ever-increasing number of cannabis forms available, which are gaining popularity for both recreational and therapeutic use. From a therapeutic perspective, oral cannabis containing Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is a promising route of administration but there is still little information about its pharmacokinetics (PK) effects in humans. The purpose of this systematic review is to provide a general overview of the available PK data on cannabis and THC after oral administration. Materials and Methods: A search of the published literature was conducted using the PubMed database to collect available articles describing the PK data of THC after oral administration in humans. Results: The literature search yielded 363 results, 26 of which met our inclusion criteria. The PK of oral THC has been studied using capsules (including oil content), tablets, baked goods (brownies and cookies), and oil and tea (decoctions). Capsules and tablets, which mainly correspond to pharmaceutical forms, were found to be the oral formulations most commonly studied. Overall, the results reflect the high variability in the THC absorption of oral formulations, with delayed peak plasma concentrations compared to other routes of administration. Conclusions: Oral THC has a highly variable PK profile that differs between formulations, with seemingly higher variability in baked goods and oil forms. Overall, there is limited information available in this field. Therefore, further investigations are required to unravel the unpredictability of oral THC administration to increase the effectiveness and safety of oral formulations in medicinal use.

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Dietary arginine uptake by the splanchnic region in adult humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.265.4.e532 ◽

1993 ◽

Vol 265 (4) ◽

pp. E532-E539 ◽

Cited By ~ 27

Author(s):

L. Castillo ◽

T. E. Chapman ◽

Y. M. Yu ◽

A. Ajami ◽

J. F. Burke ◽

...

Keyword(s):

Young Adult ◽

Intravenous Infusion ◽

Route Of Administration ◽

Healthy Young Adult ◽

Fed State ◽

Routes Of Administration ◽

Adult Men ◽

Adult Humans ◽

Plasma Arginine ◽

Infusion Protocol

To determine the uptake of dietary arginine and leucine by the splanchnic region, two experiments were carried out, each involving four healthy young adult men who received a diet supplying 1 g protein.kg-1.day-1 for 7 and 10 days before conducting a primed constant tracer infusion protocol. In study 1, subjects received for 8 h (3-h fast; 5-h fed state, achieved by a constant intragastric infusion of the diet formula) L-[5,5-2H2; guanidino-15N2]arginine ([M4]Arg), L-[guanidino-13C]arginine ([13C]Arg), and L-[5,5,5-2H3]leucine ([2H3]Leu) simultaneously by an intragastric infusion on day 7 and a repeat of this protocol on day 10 except with tracer administration given by vein. Plasma arginine fluxes were essentially the same for the two arginine tracers but differed significantly with route of administration. In study 2 the subjects received on day 7 a constant intravenous infusion of [13C]Arg and [2H3]Leu and a simultaneous intragastric infusion of [M4]Arg and [1-13C]leucine. On day 10 the routes of administration of these tracer pairs were reversed. During the fed state in study 1, splanchnic uptake of dietary arginine was 31 +/- 10 and 34 +/- 8%, based on the [13C]Arg and [M4]Arg tracers, respectively, and it was significantly higher (P < 0.01) than for leucine, which was 10 +/- 6%. In study 2, splanchnic uptake of dietary arginine, estimated from a series of tracer-protocol combinations for the fed state, was approximately 38% compared with a lower (P < 0.01) value of approximately 15% for leucine.

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Trigeminal Neuralgia: Time Course of Pain in Relation to Carbamazepine Dosing

Cephalalgia ◽

10.1111/j.1468-2982.1981.tb00015.x ◽

1981 ◽

Vol 1 (2) ◽

pp. 91-97 ◽

Cited By ~ 13

Author(s):

Torbjörn Tomson ◽

Karl Ekbom

Keyword(s):

Plasma Concentration ◽

Trigeminal Neuralgia ◽

Time Course ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Plasma Concentrations ◽

Significant Drop ◽

Idiopathic Trigeminal Neuralgia ◽

Full Effect ◽

Pain Distribution

Eight in-patients with idiopathic trigeminal neuralgia (TN) were studied while receiving carbamazepine (CBZ) treatment. The aim was to study diurnal pain distribution, its relation to CBZ dosing and plasma concentration and the effect of decreasing the dose. All pain attacks were registered by the patients at three-hour intervals. CBZ was given b.i.d. in a single blind manner with the patient unaware of dose and dose changes. Plasma concentrations of CBZ were followed every fourth hour during a period of altogether sixteen dosage intervals. The diurnal pain distribution revealed marked intra-individual similarities with pain-free nights and a significant drop in pain during mid-day hours. The latter coincided in time with the peak plasma concentration of CBZ, thus indicating an effect of plasma concentration fluctuations on pain relief. Shorter dosage intervals might therefore be beneficial in problem cases. A significant increase in pain was detected within six to nine hours after a dose reduction, whereas the full effect of the dose change seemed to be established only after one day.

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Relative bioavailability of rafoxanide following intraruminal and intra-abomasal administration in sheep

Journal of the South African Veterinary Association ◽

10.4102/jsava.v70i2.757 ◽

1999 ◽

Vol 70 (2) ◽

Author(s):

G.E. Swan ◽

H.A. Koeleman ◽

H.S. Steyn ◽

M.S.G. Mülders

Keyword(s):

Peak Plasma ◽

Plasma Concentrations ◽

Relative Bioavailability ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Routes Of Administration ◽

Parallel Group ◽

Significant Difference ◽

Rate Of Absorption ◽

Lag Period

The bioavailability of rafoxanide was compared after intraruminal and intra-abomasal administration in healthy adult sheep (n = 6) in a single dose, 2 parallel group study at 7.5 mg/kg. Rafoxanide concentrations in plasma were measured by means of HPLC analysis. Primary pharmacokinetic parameters for bioavailability and disposition of rafoxanide in plasma for both routes of administration were determined by noncompartmental and non-linear, 1-compartmental pharmacokinetic analysis, respectively. Significantly (P < 0.05) higher peak plasma concentrations (cmax) of rafoxanide and a more rapid rate of absorption (c. 3.5 times) was observed in sheep after intra-abomasal (i-a) administration compared to intraruminal (i.r.) administration. A significantly (P < 0.05) longer lag period (tlag) before absorption (6.8 + 2.9 h) occurred after i.r. than after i-a treatment (1.9 + 0.6 h). There was no significant difference (P > 0.05) in AUC, MRT and in the rates of elimination (k10-HL and t1/2b) between the i.r. and i-a routes of administration. The results of the study demonstrated the important influence of the rumino-reticulum on absorption of rafoxanide in sheep.

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Important pharmacogenomic aspects in the management of HIV/AIDS

South African Family Practice ◽

10.4102/safp.v61i1.5047 ◽

2019 ◽

Vol 61 (1) ◽

Author(s):

A. Marais ◽

E. Osuch ◽

V. Steenkamp ◽

L. Ledwaba

Keyword(s):

South African ◽

Plasma Levels ◽

Drug Exposure ◽

Peak Plasma ◽

Plasma Concentrations ◽

Metabolizing Enzymes ◽

Highly Active ◽

Adequate Dosage ◽

Hiv Aids

In managing HIV/AIDS with highly active antiretroviral agents, the historical therapeutic aim remains to maintain the plasma concentrations at a level above the half maximal inhibitory concentration (IC50) required for 50% inhibition in viral replication. Concentration dependent toxicity is often observed in patients with elevated drug exposure and high peak plasma levels in lieu of accurately calculated drug dosages. Similarly low plasma concentrations are frequently witnessed in individuals receiving adequate dosage regimens. Pharmacogenetic variations in drug metabolizing enzymes may contribute to this phenomenon. Over the last decade, knowledge about the role of pharmacogenetics in the treatment and prediction of ARV plasma levels have increased significantly. However, the extent of these genetic variations remain largely unknown in the South African population, which has sparked a renewed enthusiasm for local pharmacogenetic studies.

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