scholarly journals Pharmacokinetics of ß-d-N4-hydroxycytidine, the active metabolite of prodrug molnupiravir, in non-plasma compartments of patients with SARS-CoV-2 infection

2021 ◽  
Author(s):  
Richard FitzGerald ◽  
Laura Dickinson ◽  
Laura Else ◽  
Thomas Fletcher ◽  
Colin Hale ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Drug Candidate ◽  
Pharmacokinetic Parameters ◽  
Limit Of Quantification ◽  
Post Dose ◽  
Direct Acting Antiviral ◽  
Moderate Disease ◽  
Nasal Swabs ◽  
Nasal Secretions ◽  
Direct Acting

ABSTRACTBackgroundMolnupiravir, an orally administered prodrug of the broadly active, direct-acting antiviral, ribonucleoside analogue ß-d-N4-hydroxycytidine (NHC) is a promising COVID-19 drug candidate. We characterised the pharmacokinetics of NHC in saliva, nasal secretions and tears of patients enrolled in the phase I AGILE trial (NCT04746183) to understand its potential in preventing infection and transmission.MethodsPatients with PCR-confirmed SARS-CoV-2 infection, within 5 days of symptom onset with mild-to-moderate disease were randomised to oral molnupiravir 300, 600 or 800 mg twice daily or placebo. Plasma and non-plasma (saliva, nasal secretions and tears) samples were collected at pre-dose, 0.5, 1, 2, and 4 hours post-dose on study days 1 and 5 and molnupiravir and NHC measured by LC/MS with a lower limit of quantification of 2.5 ng/mL in all matrices. Pharmacokinetic parameters were determined by noncompartmental methods and non-plasma:plasma ratios (RNP:P; based on AUC0-4) calculated.ResultsTwelve participants (n=4 per dosing arm; 75% female) completed the study. NHC Tmax ranged between 1.00-4.00 hours for saliva (n=21) and nasal swabs (n=22) and 0.50-4.00 hours (n=17) for tears compared to 1.00-2.00 hours for plasma (n=19). Median (range) saliva RNP:P pooled across doses was 0.03 (0.01-0.11); n=16. RNP:P for nasal secretions and tears were 0.21 (0.05-0.73); n=17 and 0.22 (0.09-1.05); n=12, respectively. Non-plasma and plasma concentrations were significantly correlated (p<0.0001).ConclusionThese data provide encouraging information regarding the distribution of NHC at sites of viral transmission and have important implications for prophylactic coverage.

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.

A Bioanalytical Method for Quantification of Telmisartan in rat Plasma; Development, Validation and Application to Pharmacokinetic Study

2021 ◽  
pp. 2139-2144
Author(s):  
Khater Ahmed Saeed AL-Japairai ◽  
Bappaditya Chatterjee ◽  
Syed Mahmood ◽  
Samah Hamed Almurisi
Keyword(s):  
Pharmacokinetic Study ◽  
Limit Of Detection ◽  
Plasma Concentrations ◽  
Rat Plasma ◽  
Reversed Phase ◽  
Hplc Method ◽  
Pharmacokinetic Parameters ◽  
Sprague Dawley ◽  
Linear Calibration ◽  
Limit Of Quantification

The telmisartan was determined in a rat plasma using developed and validated a reversed-phase high performance liquid chromatographic (HPLC). The pre-treatment of the plasma sample involving liquid-liquid extraction using ethanol as the extracting solvent. The HPLC method validation has been shown a linear calibration curve over a plasma concentrations range of 0.7 to 10µg/mL with a correlation coefficient of 0.9979, the limit of detection and the limit of quantification were determined to be 0.025µg/ml and 0.07µg/ml, respectively. The precision and accuracy were in an acceptable limit. The pharmacokinetic parameters of telmisartan were adequately evaluated following a single oral dose (4mg/kg) in Sprague-Dawley rats. The results observed conclude that the developed bioanalytical HPLC method is appropriate and applicable as an analytical tool in the pharmacokinetic study of telmisartan.

scholarly journals Plasma Concentrations of Boswellic Acids in Fasting Healthy Humans Supplemented with a Water-Soluble Boswellia Extract (78% AKBA) vs. Reference Boswellia Extract (30% AKBA) (P06-005-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Barbara Davis ◽  
Krishanu Sengupta ◽  
Venkata Krishnaraju Alluri ◽  
Trimurtulu Golakoti
Keyword(s):  
Plasma Concentrations ◽  
Water Soluble ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Oral Ingestion ◽  
Post Dose ◽  
Geometric Means ◽  
Funding Sources ◽  
Healthy Humans

Abstract Objectives A randomized, open label, balanced, two-way crossover study compared the oral bioavailability and pharmacokinetic profiles of two Boswellia products standardized to 3-O-acetyl-11-Keto-β-boswellic acid (AKBA). Methods Twenty-two fasted male participants completed the study. They received a single oral-dose of water-soluble Boswellia extract 78% (LI51202F1) or the standard Boswellia extract 30% (5-Loxin) at 30 mg AKBA equivalent with 240 mL water on 2 separate occasions 12 days apart. Plasma AKBA and KBA were analyzed using a LC-MS/MS in pre- (0 hr) and post-dose (00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 04.00, 08.00, 12.00 and 24.00 hrs) blood samples. Pharmacokinetic analysis was performed using WinNonlin® version 7.0 (Pharsight corporation, USA). Results Comparative analysis of the pharmacokinetic parameters showed LI51202F1 had higher (111.11%) Cmax for AKBA vs. 5-Loxin. The bioavailability indicated by Geometric means of AUC0-t and AUC0-∞ were 25.49% and 16.13% higher in LI51202F1 than 5-Loxin. Conclusions The present study demonstrates that oral ingestion of water soluble and standard Boswellia extracts resulted in similar bioavailability. Interestingly, the water-soluble version exhibited higher Cmax and AUC values, which could be attributed to the improved solubility of LI51202F1. Funding Sources Laila Nutraceuticals.

scholarly journals Pharmacokinetic Evaluation of Darunavir Administered Once or Twice Daily in Combination with Ritonavir or the Three-Direct-Acting Antiviral Regimen of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir in Adults Coinfected with Hepatitis C and Human Immunodeficiency Viruses

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Jennifer R. King ◽  
Amit Khatri ◽  
Roger Trinh ◽  
Rolando M. Viani ◽  
Bifeng Ding ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Plasma Concentration ◽  
Historical Data ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Direct Acting Antiviral ◽  
Central Value ◽  
Human Immunodeficiency Viruses ◽  
Direct Acting ◽  
Hiv 1

ABSTRACT The three-direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin (RBV) is approved for treatment of hepatitis C virus (HCV) genotype 1 (GT1)/human immunodeficiency virus type 1 (HIV-1) coinfection. Results of a pharmacokinetic substudy of 3D and darunavir are presented. HCV/HIV-1-coinfected subjects were randomized to maintain an antiretroviral regimen with darunavir at 800 mg once daily (QD) or switched to a regimen with darunavir at 600 mg twice daily (BID). On study day 1, subjects received 3D and RBV plus darunavir for 12 weeks. Pharmacokinetic parameters were compared for darunavir and ritonavir with and without 3D (week 4 and day −1). Pharmacokinetic parameters of 3D were compared to historical data. Ten subjects received darunavir QD, and 12 subjects received darunavir BID. The central value ratios (90% confidence interval [CI]) for maximum concentrations (C max), area under the plasma concentration-time curve between 0 and 24 h postdose (AUC24), and trough plasma concentration at 24 h postdose (C 24) of darunavir administered QD with 3D versus administration of darunavir alone were 0.92 (0.72, 1.18), 0.83 (0.71, 0.98), and 0.64 (0.44, 0.93), respectively. The ratios (90% CI) for darunavir C max, AUC12, and C 12 administered BID with 3D were 0.92 (0.76, 1.12), 0.88 (0.73, 1.05), and 0.73 (0.58, 0.92), respectively. Exposures of 3D were similar to or slightly lower than those in historical data. All darunavir trough concentrations (C trough) associated with an HIV-1 RNA level of >40 copies/ml were above the darunavir 50% effective concentration (EC50) of 550 ng/ml for resistant virus. In conclusion, the 3D regimen with darunavir QD or BID did not affect darunavir C max and AUC, whereas the darunavir C trough decreased. Changes in pharmacokinetic parameters of 3D were not considered clinically significant. Episodes of intermittent HIV-1 viremia were infrequent and were not associated with darunavir C trough values below 550 ng/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT01939197.)

scholarly journals Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine

2016 ◽  
Vol 60 (10) ◽  
pp. 6244-6251 ◽  
Author(s):  
Amit Khatri ◽  
Roger Trinh ◽  
Weihan Zhao ◽  
Thomas Podsadecki ◽  
Rajeev Menon
Keyword(s):  
Geometric Mean ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Virus Genotype ◽  
Open Label ◽  
Direct Acting Antiviral ◽  
Central Value ◽  
Dose Study ◽  
Direct Acting

ABSTRACTThe direct-acting antiviral regimen of 25 mg ombitasvir–150 mg paritaprevir–100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n= 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric meanCmaxand AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric meanCmaxand AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment.

Confirmation of longer FIX activity half-life with prolonged sample collection after single doses of nonacog alfa in patients with haemophilia B

2017 ◽  
Vol 117 (06) ◽  
pp. 1052-1057 ◽  
Author(s):  
Baolai Hua ◽  
Runhui Wu ◽  
FeiFei Sun ◽  
Binyu Luo ◽  
Christine Alvey ◽  
...  
Keyword(s):  
Adverse Events ◽  
Half Life ◽  
Factor Ix ◽  
Pharmacokinetic Parameters ◽  
Sample Collection ◽  
Limit Of Quantification ◽  
Post Dose ◽  
Single Dose Study ◽  
Haemophilia B ◽  
The Impact

SummaryA multicentre, single–dose study enrolled 12 previously treated patients with moderately severe to severe (factor IX [FIX] levels ≤2 IU/dl) haemophilia B to assess FIX pharmacokinetics after nonacog alfa administration and to evaluate the impact of length of sampling time on half-life (t½). After refraining from FIX replacement for four days, patients received 50 IU/kg as an intravenous (IV) infusion over 10 minutes. Blood samples were collected predose and 0.25, 0.5, 1, 3, 6, 9, 24, 50, 72, and 96 h post dose. Tolerability and safety were assessed by monitoring adverse events and were subsequently summary tabulated. FIX activity was measured by a one-stage clotting assay with a lower limit of quantification of 0.010 IU/ml, and inhibitors to FIX were measured using the Bethesda assay. Pharmacokinetic parameters were calculated by noncompartmental analysis and were descriptively summarised. Half-life estimates were calculated first using all available data, then excluding 96-h observations (truncated at 72 h) and, finally, excluding both 72– and 96-h observations (truncated at 50 h). No patient was positive for FIX inhibitors. No treatment-emergent adverse events were reported. Prolonging the duration of the sample collection to 96 h resulted in a terminal t½ estimate of 39.6 ±7.4 h in the eight patients aged 18 years and older, which was longer than the estimates obtained using shorter periods of observation: 29.6 ± 5.5 h (truncated at 72 h) and 27.2 ± 7.0 h (truncated at 50 h). To accurately assess an adult patient’s t½, sampling should be continued for at least 96 h.

scholarly journals Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine

2016 ◽  
Vol 60 (5) ◽  
pp. 2965-2971 ◽  
Author(s):  
Amit Khatri ◽  
Sandeep Dutta ◽  
Martin Dunbar ◽  
Thomas Podsadecki ◽  
Roger Trinh ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Interactions ◽  
Healthy Volunteers ◽  
Antiretroviral Drugs ◽  
Pharmacokinetic Parameters ◽  
Direct Acting Antiviral ◽  
Drug Concentrations ◽  
Tenofovir Df ◽  
Direct Acting

ABSTRACTThe three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple-dose pharmacokinetic studies were conducted in healthy volunteers (n= 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (≤32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen.

New Epidemiologic Data Regarding Hepatitis C Virus Infection in Romania

2017 ◽  
Vol 26 (4) ◽  
pp. 381-386
Author(s):  
Mircea Manuc ◽  
Carmen M. Preda ◽  
Corneliu P. Popescu ◽  
Cristian Baicuș ◽  
Theodor Voiosu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Users ◽  
Antiviral Agent ◽  
Virologic Response ◽  
Advanced Fibrosis ◽  
Direct Acting Antiviral ◽  
Genotype 1B ◽  
Direct Acting ◽  
End Stage

Background & Aims: Literature data suggest that HCV genotype-1b is present in 93-99% of the Romanian patients infected with hepatitis C virus (HCV). We present the genotyping tests recently performed on patients with HCV and advanced fibrosis eligible for the Direct-Acting Antiviral (DAA) therapy, as well as the prevalence of these cases across Romania.Methods: The genotyping method was performed on 7,421 HCV patients with advanced fibrosis. The detection method was automatic real time PCR platform M2000 (Abbott). Every subject was introduced into a database including age, sex, county and address.Results: Genotype 1b was almost exclusively present: 7,392/7,421 (99.6%). Genotype 1b patients were 19.6% from Bucharest, 49% were males, with a median age of 60 years. Genotype non-1b was encountered in 29/7,421 subjects (0.4%), 62% were males, 69% from Bucharest and the median age was 52 years. Most of the subjects (75%) were in the 6th and 7th age decade. The prevalence of these cases varied significantly across Romanian counties: the highest was in Bucharest (61.3/105), Bihor (47/105), Iasi (46/105) and Constanța (43/105), and the lowest in Ilfov (2.8/105), Harghita (3.7/105), Covasna (5.4/105) and Maramureș (8.8/105) (p<0.001).Conclusions: Genotype 1b is encountered in 99.6% of patients with chronic hepatitis C and advanced fibrosis from Romania. The presence of genotypes non-1b is more common in Bucharest, in males and at a younger age. There are significant differences regarding the distribution of these cases across Romania: the highest rates are in Bucharest, Bihor, Iasi and Constanta.Abbreviations: BMI: body mass index; DAA: direct-acting antiviral agent; GT: genotype; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; IDU: intravenous drug users; MELD: model for end stage liver disease; NASH: non-alcoholic steatohepatitis; SVR; sustained virologic response.

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