Bioavailability of sorafenib tablets administered as a liquid suspension

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14549-e14549
Author(s):  
J. T. Lettieri ◽  
R. Dubowy ◽  
C. Xia ◽  
C. Rotolo ◽  
M. A. Zinny
Keyword(s):  
Geometric Mean ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Liquid Chromatography Mass Spectrometry ◽  
Healthy Male ◽  
Noncompartmental Analysis ◽  
Spectrometry Method ◽  
Multikinase Inhibitor ◽  
Liquid Suspension

e14549 Background: Sorafenib is a multikinase inhibitor currently approved by the FDA for the treatment of advanced renal-cell carcinoma (RCC) and unresectable hepatocellular carcinoma (HCC), and by the EMEA for the treatment of HCC and advanced RCC. Sorafenib is available as a tablet formulation. Some patients who are unable to swallow tablets have suspended sorafenib tablets in a liquid for ease of administration. We performed a study to assess whether this process alters the bioavailability of sorafenib. Methods: Twenty-six healthy male volunteers were enrolled. Utilizing a randomized, crossover design, subjects received either two 200-mg intact tablets (IT) with 8 ounces water, or two 200-mg tablets disintegrated over 10 minutes in 2 ounces of water (ST), with an additional 6 ounces of water swallowed as a rinse of the dosing vessel. Doses were separated by a 10- to 14-day washout period. Following each dose, blood samples were collected at designated times up to 144 hours after dosing for measurement of sorafenib plasma concentrations. Sorafenib was assayed by a validated liquid chromatography/mass spectrometry method. The pharmacokinetic parameters area under the curve (AUC), maximum concentration (Cmax) and time to Cmax (Tmax) were assessed by noncompartmental analysis. Results: Geometric mean (percentage coefficient of variation) or median results for these pharmacokinetic assessments are shown in the table. Conclusions: The pharmacokinetics of sorafenib, when administered as a liquid suspension of tablets in water, were similar to the pharmacokinetics of tablets swallowed whole. [Table: see text] [Table: see text]

scholarly journals Toxicity and Pharmacokinetic Studies of Lidocaine and Its Active Metabolite, Monoethylglycinexylidide, in Goat Kids

Animals ◽  
2018 ◽  
Vol 8 (8) ◽  
pp. 142
Author(s):  
Dinakaran Venkatachalam ◽  
Paul Chambers ◽  
Kavitha Kongara ◽  
Preet Singh
Keyword(s):  
Total Dose ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Lidocaine Hydrochloride ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Liquid Chromatography Mass Spectrometry ◽  
Elimination Half ◽  
The Mean ◽  
Safe Dose

This study determined the convulsant plasma concentrations and pharmacokinetic parameters following cornual nerve block and compared the results to recommend a safe dose of lidocaine hydrochloride for goat kids. The plasma concentrations of lidocaine and monoethylglycinexylidide (MGX) were quantified using liquid chromatography-mass spectrometry. A total dose of 7 mg/kg body weight (BW) was tolerated and should therefore be safe for local and regional anesthesia in goat kids. The mean plasma concentration and mean total dose that produced convulsions in goat kids were 13.59 ± 2.34 µg/mL and 12.31 ± 1.42 mg/kg BW (mean ± S.D.), respectively. The absorption of lidocaine following subcutaneous administration was rapid with Cmax and Tmax of 2.12 ± 0.81 µg/mL and 0.33 ± 0.11 h, respectively. The elimination half-lives (t½λz) of lidocaine hydrochloride and MGX were 1.71 ± 0.51 h and 3.19 ± 1.21 h, respectively. Injection of 1% lidocaine hydrochloride (0.5 mL/site) was safe and effective in blocking the nerves supplying horn buds in goat kids.

scholarly journals Increased tenofovir monoester concentrations in patients receiving tenofovir disoproxil fumarate with ledipasvir/sofosbuvir

2019 ◽  
Vol 74 (8) ◽  
pp. 2360-2364 ◽  
Author(s):  
Kristina M Brooks ◽  
Jose R Castillo-Mancilla ◽  
Joshua Blum ◽  
Ryan Huntley ◽  
Samantha MaWhinney ◽  
...  
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Clinical Relevance ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Dried Blood Spots ◽  
Pharmacokinetic Parameters ◽  
Post Dose ◽  
P Values ◽  
Hydrolysis Of ◽  
Tenofovir Diphosphate

AbstractBackgroundIntracellular tenofovir diphosphate concentrations are markedly increased in HIV/HCV coinfected individuals receiving tenofovir disoproxil fumarate (TDF) with sofosbuvir-containing treatment. Sofosbuvir may inhibit the hydrolysis of TDF to tenofovir, resulting in increased concentrations of the disoproxil or monoester forms, which may augment cell loading. We sought to quantify tenofovir disoproxil and monoester concentrations in individuals receiving TDF with and without ledipasvir/sofosbuvir.MethodsHIV/HCV coinfected participants receiving TDF-based therapy were sampled pre-dose and 1 and 4 h post-dose prior to and 4 weeks after initiating ledipasvir/sofosbuvir. Tenofovir disoproxil was not detectable. Tenofovir monoester in plasma and tenofovir diphosphate in PBMC and dried blood spots (DBS) were quantified using LC-MS/MS. Geometric mean ratios (week 4 versus baseline) and 95% CIs were generated for the pharmacokinetic parameters. P values reflect paired t-tests.ResultsTen participants had complete data. At baseline, geometric mean (95% CI) tenofovir monoester plasma concentrations at 1 and 4 h post-dose were 97.4 ng/mL (33.0–287.5) and 0.74 ng/mL (0.27–2.06), respectively. With ledipasvir/sofosbuvir, tenofovir monoester concentrations at 4 h post-dose were 5.02-fold higher (95% CI 1.40–18.05; P = 0.019), but did not significantly differ at 1 h post-dose (1.72-fold higher, 95% CI 0.25–11.78; P = 0.54), possibly due to absorption variability. Tenofovir diphosphate in PBMC and DBS were increased 2.80-fold (95% CI 1.71–4.57; P = 0.001) and 7.31-fold (95% CI 4.47–11.95; P < 0.0001), respectively, after 4 weeks of ledipasvir/sofosbuvir.ConclusionsTenofovir monoester concentrations were increased in individuals receiving TDF with ledipasvir/sofosbuvir, consistent with inhibition of TDF hydrolysis. Additional studies are needed to determine the clinical relevance of this interaction.

Exposure to chloroquine in male adults and children aged 9–11 years with malaria due to Plasmodium vivax

2020 ◽  
Author(s):  
Michelle Valeria Dias Ferreira Vieira ◽  
José Luiz Fernandes Vieira
Keyword(s):  
Plasmodium Vivax ◽  
High Performance ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Time Profile ◽  
Pharmacokinetic Parameters ◽  
Older Children ◽  
Asexual Blood Stage ◽  
Adults And Children ◽  
A Prospective Study

Abstract Background Chloroquine is effective against the asexual blood stage of Plasmodium vivax. A high proportion of children are underdosed with the drug, but there are no studies comparing chloroquine exposure in adults and children aged 8–11 years old. The present study intends to compare these populations using the area under the curve (AUC) derived from the plasma concentration-time profile in patients with P. vivax. Methods A prospective study of cases was performed on male children (aged 9–11 years) and adults with vivax malaria. Blood samples were collected after several days of treatment. Chloroquine was measured by high-performance liquid chromatography. A non-compartmental pharmacokinetic model was used to calculate the pharmacokinetic parameters of the drug. Results A total of 20 children and 25 adults were included in the study. Plasma concentrations of chloroquine in older children ranged from 67 to 1112 ng/ml, and in adults the value ranged from 74 to 1147 ng/ml. The AUC to the last measurable concentration and to infinite was significantly lower in children than in adults, indicating a lower exposure to the drug. Conclusion These data demonstrate lower exposure to chloroquine in children, which corroborates the importance of optimising the doses of chloroquine in the study age band to ensure adequate exposure to the drug.

scholarly journals Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Wendy Ankrom ◽  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Adedayo Adedoyin ◽  
Li Fan ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Transcriptase Inhibitor ◽  
Maximum Plasma ◽  
Minor Effect ◽  
Minimal Impact

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ≥80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0–∞), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.)

scholarly journals Are Prophylactic and Therapeutic Target Concentrations Different?: the Case of Lopinavir-Ritonavir or Lamivudine Administered to Infants for Prevention of Mother-to-Child HIV-1 Transmission during Breastfeeding

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Frantz Foissac ◽  
Jörn Blume ◽  
Jean-Marc Tréluyer ◽  
Thorkild Tylleskär ◽  
Chipepo Kankasa ◽  
...  
Keyword(s):  
South African ◽  
Population Analysis ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Breastfed Infants ◽  
Trough Concentrations ◽  
Therapeutic Doses ◽  
Mother To Child ◽  
Hiv 1

ABSTRACT The ANRS 12174 trial assessed the efficacy and tolerance of lopinavir (LPV)-ritonavir (LPV/r) prophylaxis versus those of lamivudine (3TC) prophylaxis administered to breastfed infants whose HIV-infected mothers were not on antiretroviral therapy. In this substudy, we assessed LPV/r and 3TC pharmacokinetics to evaluate the percentage of infants with therapeutic plasma concentrations and to discuss these data in the context of a prophylactic treatment. Infants from the South African trial site underwent blood sampling for pharmacokinetic study at weeks 6, 26, and 38 of life. We applied a Bayesian approach to derive the 3TC and LPV pharmacokinetic parameters on the basis of previously published pharmacokinetic models for HIV-infected children. We analyzed 114 LPV and 180 3TC plasma concentrations from 69 infants and 92 infants, respectively. A total of 30 LPV and 20 3TC observations were considered missing doses and discarded from the Bayesian analysis. The overall population analysis showed that 30 to 40% of the infants did not reach therapeutic targets, regardless of treatment group. The median LPV trough concentrations at weeks 6, 26, and 38 were 2.8 mg/liter (interquartile range [IQR], 1.7 to 4.4 mg/liter), 5.6 mg/liter (IQR, 3.2 to 7.7 mg/liter), and 3.4 mg/liter (IQR, 2.3 to 7.3 mg/liter), respectively. The median 3TC area under the curve from 0 to 12 h after the last drug intake were 5.6 mg · h/liter (IQR, 4.1 to 7.8 mg · h/liter), 5.9 mg · h/liter (IQR, 5.1 to 7.5 mg · h/liter), and 7.3 mg · h/liter (IQR, 4.9 to 8.5 mg · h/liter) at weeks 6, 26, and 38, respectively. Use of the therapeutic doses recommended by the WHO would have resulted in a higher proportion of infants achieving the targets. However, no HIV-1 infection was reported among these infants. These results suggest that the prophylactic targets for both 3TC and LPV may be lower than the therapeutic ones. For treatment, the WHO dosing guidelines should be suitable to maintain values above the therapeutic pharmacokinetic targets in most infants. (This study has been registered at ClinicalTrials.gov under identifier NCT00640263.)

scholarly journals Pharmacokinetics of Liposomal Amphotericin B for Injection in Chinese Healthy Subjects Based on a Bioequivalence Study

2021 ◽  
Author(s):  
Xueyuan Zhang ◽  
Huanhuan Qi ◽  
Manman Wang ◽  
Yuhuan Ji ◽  
Chunlei Li ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Liposomal Amphotericin B ◽  
Pharmacokinetic Parameters ◽  
Healthy Population ◽  
Open Label ◽  
Liposomal Form

Abstract Purpose: The aim of this study was to evaluate the pharmacokinetic characteristics and safety of Liposomal Amphotericin B for injection in healthy Chinese volunteers based on a pilot bioequivalence clinical trial between a generic formulation and Ambisome ® Methods: This randomized, two sequence, open label, single dose,two period crossover study was conducted in healthy volunteers at the dose of 2mg kg Blood samples were collected at pre defined time points up to 674 h after the start of the 2 h infusion. Plasma concentrations of total, unencapsulated and encapsulated amphotericin B were determined. Pharmacokinetic parameters were calculated using non compartmental model . The formulations were considered bioequivalent if the 90% confidence interval ls (CIs) of the geometric mean ratio of C max and AUC of both products for free and encapsulated amphotericin B were within80.00 1 25.00 for L n transformed data. Results and conclusion: All the 12subjects completed the two period study , no subjects withdrew the study. The plasma pharmacokinetic profile of liposomal amphotericin B based on free, encapsulated and total amphotericin B demonstrated the characteristics of a three compartment al model. The majority drug in the circulating system after IV infusion of liposomal amphotericin B is remained liposomal form . Pharmacokinetic behaviors in Chinese population w ere consistent with that in western healthy population based on total and unbound amphotericin B concentrations in plasma. The generic liposomal amphotericin B for injection is bioequivalent to Ambisome ® in terms of the Pharmacokinetic parameters for free, encapsulated and total amphotericin B. Trial registration number at National Medical Products Administration CTR20200885 . Date of registration: May 22 , 20 2 0.

Relative bioequivalence of amoxicillin dissolved in breast milk

2013 ◽  
Vol 99 (3) ◽  
pp. 258-261
Author(s):  
Parvaneh Yazdani-Brojeni ◽  
Facundo Garcia-Bournissen ◽  
Hisaki Fujii ◽  
Reo Tanoshima ◽  
Shinya Ito
Keyword(s):  
Breast Milk ◽  
Human Milk ◽  
Healthy Adult ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Fasting State ◽  
Oral Antibiotics ◽  
Liquid Chromatography Mass Spectrometry ◽  
Antibiotics Use ◽  
Adult Volunteers

BackgroundOral antibiotics use in infants in developing countries is challenging because liquid formulations are often unavailable. However, dissolving solid formulation of drugs in water poses a risk of gastrointestinal infection. Although mother's milk may be a potential vehicle, no evidence exists to indicate that antibiotics dissolved in human milk are bioequivalent to those dissolved in water. Therefore, we compared pharmacokinetic parameters of an orally administered antibiotic, amoxicillin, dissolved in human milk, to those of water-dissolved amoxicillin.MethodsA pharmacokinetic study was conducted in 16 healthy adult volunteers in a randomised crossover design. Marketed amoxicillin powder for suspension was dissolved in either human milk or water at a final concentration of 50 mg/mL, and 10 mL was given orally in a fasting state. Timed blood samples were obtained and plasma amoxicillin was quantified using liquid chromatography-mass spectrometry.FindingsResults showed that pharmacokinetic parameters, including area-under-the-curve, Cmax and half-life of the water-based and milk-based amoxicillin administration were not significantly different. 90% CIs of the ratios of these parameters in concomitant breast milk administration to those of water were within 89% and 116%, suggesting they are bioequivalent (defined as a range between 80% and 125%).InterpretationWe conclude that oral administration of amoxicillin dissolved in human milk at 50 mg/mL results in pharmacokinetics profiles comparable to amoxicillin dissolved in water. Pharmaceutical interactions between amoxicillin and breast milk are unlikely, suggesting no need to modify dosing schedules.

Pharmacokinetic comparison of two buprenorphine formulations after buccal administration in healthy male cats

2017 ◽  
Vol 20 (4) ◽  
pp. 312-318 ◽  
Author(s):  
Brett M Gulledge ◽  
Kristen M Messenger ◽  
Karen K Cornell ◽  
Heather Lindell ◽  
Chad W Schmiedt
Keyword(s):  
Liquid Chromatography ◽  
Maximum Concentration ◽  
High Performance ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Storage Condition ◽  
Healthy Male ◽  
Limit Of Quantification ◽  
Significant Difference ◽  
Extent Of Absorption

Objectives The objective of this study was to compare the pharmacokinetics of compounded and commercially available aqueous formulations of buprenorphine after a single buccal dose to healthy cats and to evaluate the concentrations of a compounded buprenorphine solution over 21 days when stored at room temperature (RT; 22–24°C) with exposure to light or when refrigerated at 4°C while protected from light. Methods Six young healthy male cats were administered single buccal doses of compounded and commercially available formulations of buprenorphine (0.03 mg/kg) using a randomized, blinded, two-period crossover design. Blood samples were obtained over a 24 h period and plasma buprenorphine concentrations were determined using ultra-high-pressure liquid chromatography with mass spectrometry detection. Three batches of the compounded formulation were stored at RT or 4°C and aliquots were evaluated over 21 days for buprenorphine concentration using high-performance liquid chromatography with fluorescence detection. Results Plasma concentrations of buprenorphine were above the limit of quantification up to 6 h in some cats and up to 3 h in all cats. The area under the curve was significantly less for the compounded formulation ( P = 0.004). A significant difference was not detected between formulations for time to maximum concentration ( P = 0.11), maximum concentration ( P = 0.06), half-life ( P = 0.88) and mean residence time ( P = 0.57). Buprenorphine concentration in the compounded formulation was not affected by storage condition or time and remained between 90% and 110% of the target concentration at all time points. Conclusions and relevance A buprenorphine solution prepared from sublingual tablets is absorbed after buccal administration in healthy cats. The extent of absorption is significantly less than that of the commercially available formulation. The compounded solution maintains an acceptable buprenorphine concentration for at least 21 days when stored at RT or refrigerated.

Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients

2018 ◽  
Vol 34 (10) ◽  
pp. 1766-1772 ◽  
Author(s):  
Lama M Hsaiky ◽  
Francine D Salinitri ◽  
Judy Wong ◽  
Sin-Ling T Jennings ◽  
Neha H Desai ◽  
...  
Keyword(s):  
Half Life ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Optimal Dose ◽  
Hemodialysis Patients ◽  
Pharmacokinetic Parameters ◽  
Intermittent Hemodialysis ◽  
Pharmacokinetic Studies ◽  
Open Label ◽  
Serious Adverse Events

Abstract Background Previous pharmacokinetic studies demonstrated an increase in serum ertapenem concentrations with decreasing kidney function, including patients receiving renal replacement therapy. This study evaluated the pharmacokinetic parameters of ertapenem in patients receiving hemodialysis. Methods This prospective, single-center, open-label study examined the pharmacokinetics of a single intravenous (IV) dose of ertapenem 1 g in seven hospitalized noninfected patients undergoing hemodialysis. Blood samples were collected prior to ertapenem administration and at 0.5, 1, 2, 6, 12 and 48 hours (h) after administration. Ertapenem concentrations were determined by validated liquid chromatography mass spectrometry assay. Results Following an IV bolus of 1 g ertapenem, plasma concentrations declined relatively slowly with a mean ±standard deviation (SD) elimination half-life of 19.3 ±6.6 h. Plasma concentrations were similar in all subjects, with maximum mean plasma concentration observed of 343±48 µg/mL postdose. The mean ±SD values for systemic plasma clearance (CL) and volume of distribution at steady state (Vss) were 2±0.5 mL/min and 3295±1187 mL, respectively. The area under the curve for 0 h–∞ (AUCinf) was 7494 ±1424 h•µg/mL. No gender effect was observed and no serious adverse events were reported. Conclusions Ertapenem half-life was prolonged in hemodialysis patients. Considering the nonrenal clearance and the expected 70% removal with high-efficacy hemodialysis, the dose of 1 g ertapenem, three times weekly, after hemodialysis may produce pharmacodynamically sufficient exposure for potential antimicrobial efficacy. Further studies are warranted to assess the clinical efficacy and safety of this dose with prolonged duration of therapy.

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