scholarly journals Pharmacokinetics of tenofovir monoester and association with intracellular tenofovir diphosphate following single-dose tenofovir disoproxil fumarate

2019 ◽  
Vol 74 (8) ◽  
pp. 2352-2359 ◽  
Author(s):  
Kristina M Brooks ◽  
Mustafa E Ibrahim ◽  
Jose R Castillo-Mancilla ◽  
Samantha MaWhinney ◽  
Keisha Alexander ◽  
...  
Keyword(s):  
Single Dose ◽  
Tenofovir Disoproxil Fumarate ◽  
Geometric Mean ◽  
Bioequivalence Study ◽  
Pharmacokinetic Profile ◽  
Dried Blood Spots ◽  
Cellular Pharmacology ◽  
Hydrolysis Of ◽  
Tenofovir Diphosphate

Abstract Background Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported. Methods Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models. Results Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) Tmax of 0.5 h (0.25–2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0–4 was 93.3 ng·h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng·h/mL (30.0%). Tenofovir monoester AUC0–∞ (but not tenofovir AUC0–∞) was a significant predictor of tenofovir diphosphate in both PBMC (P = 0.015) and DBS (P = 0.005), increasing by 3.8% (95% CI 0.8%–6.8%) and 4.3% (95% CI 1.5%–7.2%), respectively, for every 10 ng·h/mL increase in tenofovir monoester. Conclusions Tenofovir monoester Cmax and AUC0–4 were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.

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.

Bioequivalence Study of Rivastigmine 6 mg Capsules (Single Dose) in Healthy Volunteers

2017 ◽  
Vol 32 (6) ◽  
pp. 360-366
Author(s):  
Dhiraj Abhyankar ◽  
Ashish Shedage ◽  
Milind Gole ◽  
Preeti Raut
Keyword(s):  
Single Dose ◽  
Standard Deviation ◽  
Geometric Mean ◽  
Bioequivalence Study ◽  
Open Label ◽  
Time Curve ◽  
Healthy Men ◽  
Time Zero ◽  
Concentration Time ◽  
To Receive

Objective: To assess the bioequivalence of generic formulation of rivastigmine (test) and Exelon (reference). Methods: This randomized, open-label, 2-period, single-dose, 2-treatment, 2-sequence, crossover study was conducted in 40 healthy men under fed condition. Participants were randomized to receive a single dose of Exelon or rivastigmine capsule. Results: A total of 31 participants completed the study. Area under the concentration–time curve from time zero to time t (AUC0- t) and area under the concentration–time curve from time zero to infinity (AUC0-∞) for Exelon (mean [standard deviation], h·ng/mL) were 126.40 (56.95) and 129.46 (59.94), respectively, while they were 122.73 (43.46) and 125.08 (45.39) for rivastigmine. Geometric mean ratios of rivastigmine/Exelon were 99.17% for AUC0- t, 98.81% for AUC0-∞, and 105% for maximum observed plasma concentration ( Cmax). The 90% confidence intervals (CIs) were 94.14% to 104.46%, 93.77% to 104.12%, and 93.08% to 118.44%, respectively. Both formulations were well tolerated. Conclusion: The generic and reference formulations were bioequivalent, as the 90% CIs for Cmax, AUC0- t, and AUC0-∞ were within the range of 80% to 125%.

Pharmacokinetics of fixed-dose combination of tenofovir disoproxil fumarate, lamivudine, and efavirenz: results of a randomized, crossover, bioequivalence study

2016 ◽  
Vol 28 (5) ◽  
pp. 491-498 ◽  
Author(s):  
Dhiraj Abhyankar ◽  
Ashish Shedage ◽  
Milind Gole ◽  
Preeti Raut
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Geometric Mean ◽  
Bioequivalence Study ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Geometric Mean Ratio ◽  
Open Label ◽  
Post Dose ◽  
Dose Combination ◽  
The Individual

The objective of this study was to assess the bioequivalence between a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/efavirenz 300/300/600 mg and the individual innovator products. A randomized, balanced, open-label, two-sequence, two-treatment, two-period, single dose, crossover study in 48 healthy adults was conducted. Dosing was separated by a washout period of 32 days. Twenty-seven blood samples were collected in each period from pre-dose to 72 h post-dose. The data of 45 subjects were analyzed for pharmacokinetics and safety. Ninety percent CIs of geometric mean ratio on Cmax, AUC0–t, and AUC0-inf for tenofovir and lamivudine and on Cmax and AUC0-72 for efavirenz were within the acceptance criteria (80–125%). For tenofovir disoproxil fumarate, the Tmax, Kel, and t1/2 values for the test and reference products were 1.02 versus 0.91 h, 0.04 versus 0.04/h, 18.67 versus 18.46 h, respectively. For lamivudine, the Tmax, Kel, and t1/2 values were: 1.38 versus 1.30 h, 0.21 versus 0.19/h, 3.44 versus 3.91 h, respectively. For efavirenz, the Tmax values for the test and reference products were 3.71 and 3.65 h, respectively. Both the treatments were well tolerated. Our findings suggest that the tested formulation is bioequivalent to the innovators’ formulations, and both treatments were well tolerated.

scholarly journals Factors associated with tenofovir diphosphate concentrations in dried blood spots in persons living with HIV

2020 ◽  
Vol 75 (6) ◽  
pp. 1591-1598 ◽  
Author(s):  
Ryan P Coyle ◽  
Mary Morrow ◽  
Stacey S Coleman ◽  
Edward M Gardner ◽  
Jia-Hua Zheng ◽  
...  
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Dried Blood Spots ◽  
Future Research ◽  
Art Adherence ◽  
Factors Associated ◽  
Blood Spots ◽  
Persons Living With Hiv ◽  
Clinical Covariates ◽  
Living With Hiv ◽  
Tenofovir Diphosphate

Abstract Objectives To determine factors associated with interindividual variability in tenofovir diphosphate (TFV-DP) concentrations in dried blood spots (DBSs) among persons living with HIV (PLWH). Methods PLWH who were at least 18 years old and taking tenofovir disoproxil fumarate-containing ART were prospectively recruited and enrolled from a clinical cohort and followed longitudinally (up to three visits over 48 weeks). With log-transformed TFV-DP concentrations in DBSs as the outcome, mixed-model regression analyses were used to assess associations between self-reported 3 month ART adherence, race and other clinical covariates (gender, age, BMI, CD4+ T cell count, estimated glomerular filtration rate, haematocrit, duration on current ART and anchor drug class) on TFV-DP in DBSs. Results Five hundred and twenty-seven participants (1150 person-visits) were analysed. Adjusting for race and other clinical covariates, every 10% increase in self-reported 3 month ART adherence was associated with an average TFV-DP concentration increase in DBSs of 28% (95% CI: 24%–32%; P &lt; 0.0001). In the same model, female participants had 20% (95% CI: 3%–40%; P = 0.02) higher TFV-DP concentrations in DBSs, compared with male participants, and every 1 kg/m2 increase in BMI was associated with a decrease in TFV-DP concentration in DBSs by 2% (95% CI: −3% to −1%; P &lt; 0.0001). Conclusions Individual patient characteristics were predictive of TFV-DP concentration in DBSs in PLWH receiving tenofovir disoproxil fumarate-based ART. Future research to incorporate these predictors into the interpretation of this ART adherence biomarker, and to establish whether these associations extend to PLWH taking tenofovir alafenamide-containing ART, is needed.

scholarly journals Plasma and intracellular pharmacokinetics of tenofovir disoproxil fumarate and emtricitabine in transgender women receiving feminizing hormone therapy

2020 ◽  
Vol 75 (5) ◽  
pp. 1242-1249 ◽  
Author(s):  
Lauren R Cirrincione ◽  
Anthony T Podany ◽  
Joshua P Havens ◽  
Sara H Bares ◽  
Shetty Ravi Dyavar ◽  
...  
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Geometric Mean ◽  
Increased Risk ◽  
And Gender ◽  
Hiv Acquisition ◽  
Risk Of Hiv Acquisition ◽  
Exposure Prophylaxis ◽  
Tissue Compartments ◽  
Tenofovir Diphosphate ◽  
Hiv Negative

Abstract Background Transwomen have an increased risk of HIV acquisition compared with other adults. Drug–drug interactions between pre-exposure prophylaxis (PrEP) and gender-affirming therapy are cited as a reason for poor PrEP uptake among transwomen. We evaluated plasma tenofovir and emtricitabine pharmacokinetics and their active intracellular anabolites, tenofovir-diphosphate and emtricitabine-triphosphate, in transwomen receiving feminizing hormones. Methods We enrolled HIV-negative transwomen (≥19 years) not receiving PrEP. Participants took oral tenofovir disoproxil fumarate/emtricitabine 300/200 mg daily for 14 days. Plasma was collected at 0 h (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 12 h on day 14 post-tenofovir disoproxil fumarate/emtricitabine dose. The plasma AUC0–24 was calculated using the trapezoidal rule and compared with historical HIV-negative cisgender adults as geometric mean ratios (GMRs, 90% CI). Secondarily, tenofovir-diphosphate and emtricitabine-triphosphate from PBMCs collected at 0 h and 12 h were reported descriptively as geometric means (90% CI). Clinical trials registration: NCT03270969. Results Among 15 transwomen (mean age 32 years), geometric mean tenofovir and emtricitabine plasma AUC0–24 were lower compared with controls: tenofovir, 2.10 versus 2.76 mg·h/L, GMR 0.76 (0.65–0.90), P = 0.01; emtricitabine, 9.15 versus 10.64 mg·h/L, GMR 0.86 (0.75–0.98), P = 0.07. Tenofovir-diphosphate and emtricitabine-triphosphate concentrations were higher than previously reported in the literature: 167.1 (146.6–190.5) fmol/106 cells and 15.4 (13.8–17.3) pmol/106 cells, respectively. Conclusions We observed lower plasma tenofovir and emtricitabine concentrations in transwomen compared with historical cisgender adults, yet intracellular tenofovir-diphosphate and emtricitabine-triphosphate concentrations were higher than previously reported in PBMCs. Understanding the differences of PrEP pharmacokinetics in plasma and tissue compartments and the resultant impact on efficacy remains important for transwomen.

scholarly journals Single-Dose and Steady-State Pharmacokinetics of Tenofovir Disoproxil Fumarate in Human Immunodeficiency Virus-Infected Children

2004 ◽  
Vol 48 (1) ◽  
pp. 124-129 ◽  
Author(s):  
Rohan Hazra ◽  
Frank M. Balis ◽  
Antonella N. Tullio ◽  
Ellen DeCarlo ◽  
Carol J. Worrell ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Single Dose ◽  
Steady State ◽  
Antiretroviral Therapy ◽  
Tenofovir Disoproxil Fumarate ◽  
Geometric Mean ◽  
Transcriptase Inhibitor ◽  
Time Curve ◽  
Immunodeficiency Virus ◽  
Tenofovir Df

ABSTRACT Tenofovir disoproxil fumarate (DF) is a potent nucleotide analog reverse transcriptase inhibitor approved for the treatment of human immunodeficiency virus (HIV)-infected adults. The single-dose and steady-state pharmacokinetics of tenofovir were evaluated following administration of tenofovir DF in treatment-experienced HIV-infected children requiring a change in antiretroviral therapy. Using increments of tenofovir DF 75-mg tablets, the target dose was 175 mg/m2; the median administered dose was 208 mg/m2. Single-dose pharmacokinetics were evaluated in 18 subjects, and the geometric mean area under the concentration-time curve from 0 h to ∞ (AUC0-∞) was 2,150 ng · h/ml and the geometric mean maximum concentration (C max) was 266 ng/ml. Subsequently, other antiretrovirals were added to each patient's regimen based upon treatment history and baseline viral resistance results. Steady-state pharmacokinetics were evaluated in 16 subjects at week 4. The steady-state, geometric mean AUC for the 24-h dosing interval was 2,920 ng · h/ml and was significantly higher than the AUC0-∞ after the first dose (P = 0.0004). The geometric mean C max at steady state was 302 ng/ml. Tenofovir DF was generally very well tolerated. Steady-state tenofovir exposures in children receiving tenofovir DF-containing combination antiretroviral therapy approached values seen in HIV-infected adults (AUC, ∼3,000 ng · h/ml; C max, ∼300 ng/ml) treated with tenofovir DF at 300 mg.

scholarly journals Tenofovir Diphosphate in Dried Blood Spots Is Strongly Associated With Viral Suppression in Individuals With Human Immunodeficiency Virus Infections

2018 ◽  
Vol 68 (8) ◽  
pp. 1335-1342 ◽  
Author(s):  
Jose R Castillo-Mancilla ◽  
Mary Morrow ◽  
Ryan P Coyle ◽  
Stacey S Coleman ◽  
Edward M Gardner ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Suppression ◽  
Geometric Mean ◽  
Dried Blood Spots ◽  
Hiv Treatment ◽  
Virologic Suppression ◽  
Blood Spots ◽  
Persons Living With Hiv ◽  
Immunodeficiency Virus ◽  
Tenofovir Diphosphate

Abstract Background Although tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a predictor of adherence and pre-exposure prophylaxis efficacy, its utility in human immunodeficiency virus (HIV) treatment remains unknown. Methods DBS for TFV-DP were collected up to 3 times over 48 weeks in persons living with HIV (PLWH) who were receiving TFV disoproxil fumarate (TDF)-based therapy. Log-transformed baseline TFV-DP was compared using t-tests or analyses of variance; generalized estimating equations were used to estimate the adjusted odds ratio (aOR) of viral suppression (&lt;20 copies/mL) based on the TFV-DP concentration at the study visit. Results We analyzed 1199 DBS from 532 participants (76 female; 101 Black, 101 Hispanic). Among the virologically-suppressed participants at baseline (n = 347), TFV-DP was lower in Blacks (geometric mean 1453, 95% confidence interval [CI] 1291–1635) vs Whites (1793, 95% CI 1678–1916; P = .002) and Hispanics (1760, 95% CI 1563–1982; P = .025); in non-boosted (1610, 95% CI 1505–1723) vs. boosted (1888, 95% CI 1749–2037; P = .002) regimens; and in non-nucleoside reverse transcription inhibitor–based (1563, 95% CI 1432–1707) vs. boosted protease inhibitor–based (1890, 95% CI 1704–2095; P = .006) and multiclass-based (1927, 95% CI 1650–2252; P = .022) regimens. The aOR of virologic suppression, after adjusting for age, gender, race, body mass index, estimated glomerular filtration rate, CD4+ T-cell count, antiretroviral drug class and duration of therapy, was 73.5 (95% CI 25.7–210.5; P &lt; .0001) for a TFV-DP concentration ≥1850 fmol/punch compared to &lt;350 fmol/punch. Conclusions TFV-DP in DBS is strongly associated with virologic suppression in PLWH on TDF-based therapy and is associated with certain participant characteristics. Further research is required to evaluate this drug adherence and exposure measure in clinical practice. Clinical Trials Registration NCT02012621.

scholarly journals Bioequivalence study of different brands of vildagliptin in healthy human subjects

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mahaveer Sharma ◽  
S. S. Agrawal
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Geometric Mean ◽  
Bioequivalence Study ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Healthy Human ◽  
Single Dose Study ◽  
Dipeptidyl Peptidase 4 ◽  
Significant Difference

Abstract Background Vildagliptin is a dipeptidyl peptidase-4 inhibitor used to treat diabetes mellitus. No bioequivalence study data have been published for the Indian population comparing bioequivalence of vildagliptin brands Galvus, Zomelis, and Jalra. This study aimed to evaluate the bioequivalence between three brands of vildagliptin 50 mg tablet (test 1, Zomelis; test 2, Jalra; and reference, Galvus) and to compare these test formulations with the reference formulation to meet the regulatory requirements of bioequivalence of CDSCO, India. The study was conducted in the clinical research center of the college after enrolling 12 healthy volunteers. This study was a single-dose, randomized, open-label, balanced, three treatment, three period, under fasting condition in 12 adult healthy volunteers. After overnight fasting, the subjects received a single dose of either of any three brands of the vildagliptin tablet (T1—test 1; T2—test 2; and R—reference). The washout period was 7 days. Randomization was in the way of T1T2R in the first period, T2T1R in the second period, and RT1T2 in the third period. Blood samples were collected, after that drug concentration in the plasma was measured with the help of HPLC. Outcome measures 90% confidence interval of the geometric mean ratios (test/reference) for the LnCmax, LnAUC0-t, and LnAUC0-∞ was calculated. Results The AUC0-t was 1390.03, 1401.50, and 1409.37 ng h/ml for the T1, T2, and R, respectively. Cmax was 287.89, 287.41, and 285.17 ng/ml for the T1, T2, and R, respectively. AUC0-∞ was 1452.03, 1467.59, and 1473.53 ng h/ml for the T1, T2, and R, respectively. No significant difference was observed in the pharmacokinetic parameters between the T1, T2, and R. The geometric mean ratios for T1/R for LnCmax, LnAUC0-t, and LnAUC0-∞ were 1.0014 (90% CI, 1.0002–1.0026), 0.9992 (90% CI, 0.9971–1.0013), and 0.9994 (90% CI, 0.9973–1.0016), respectively. For the T2/R, geometric mean ratios for LnCmax, LnAUC0-t, and LnAUC0-∞ were 1.0003 (90% CI, 0.9992–1.0013), 0.9988 (90% CI, 0.9969–1.0008), and 0.9985 (90% CI, 0.9961–1.0010), respectively. Conclusion In this single-dose study involving Indian healthy volunteers under fasting conditions, the three brands of vildagliptin (Zomelis, Jalra, and Galvus) were bioequivalent as per the bioequivalence criterion of CDSCO, India.

P–587 Highly purified human menopausal gonadotrophin (HP-hMG, Menopur) as a ready-to-use solution for injection in pre-filled pen is bioequivalent to HP-hMG powder for reconstitution

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
D M Jonker ◽  
M Koch ◽  
P Larsson ◽  
A Ravi ◽  
B B Rasmussen ◽  
...  
Keyword(s):  
Single Dose ◽  
Confidence Intervals ◽  
Geometric Mean ◽  
Bioequivalence Study ◽  
Reproductive Age ◽  
Efficacy And Safety ◽  
Post Dose ◽  
Registration Number ◽  
Randomised Controlled ◽  
Meta Analyses

Abstract Study question Are serum FSH levels after single subcutaneous dosing of HP-hMG in a liquid formulation and a powder formulation bioequivalent? Summary answer The 90% CIs for the geometric mean ratios of serum FSH AUCt and Cmax were both within 0.8000–1.2500, thus the two formulations are bioequivalent. What is known already For several decades, HP-hMG (Menopur) has been used for the treatment of infertility; its efficacy and safety compared to other gonadotropins have been consistently demonstrated in several prospective, randomised controlled trials and meta-analyses (Deeks et al 2018; Bordewijk et al 2019). Menopur powder for reconstitution is available in multidose and single dose formulations. Up to 3 single dose vials (each containing 75 IU) may be dissolved into 1 mL solvent for administration. Recently, and for the first time, Menopur has been successfully formulated in a stable, ready-to-use solution for injection, which may be administered by a pre-filled pen. Study design, size, duration This was a randomised, two-way crossover, single dose, bioequivalence trial comparing Menopur liquid injected by pre-filled pen, with Menopur powder injected by conventional syringe and needle. The primary endpoints were AUCt and Cmax of baseline-adjusted FSH. Pituitary-suppressed, healthy women were randomised to receive one treatment sequence including a single subcutaneous injection of 450 IU Menopur liquid (600 IU/0.96 mL) and of 450 IU Menopur powder by two subcutaneous injections of 225 IU in 1 mL. Participants/materials, setting, methods Blood samples were collected pre- and post-dose, until 9 days after each injection. The PK parameters of FSH and hCG were assessed by noncompartmental methods with adjustment for endogenous pre-dose levels. Highly sensitive and specific electrochemiluminescence immunoassays were used for quantification and the LLOQ of the FSH and hCG assays were 1.47 mIU/mL and 0.5 mIU/mL, respectively, and the total validated CV was within 5% for both assays. Main results and the role of chance In total, 76 women were randomised and 56 completed the trial. The main reason for discontinuation was insufficient pituitary suppression prior to the second administration of HP-hMG. The mean FSH and hCG serum concentration-time profiles were comparable between the two HP-hMG formulations. The geometric mean ratios and 90% confidence intervals of FSH for HP-hMG liquid versus HP-hMG powder were 1.12 [1.0562; 1.1889] for AUCt and 1.17 [1.0946; 1.2490] for Cmax, showing that the two formulations were bioequivalent. Maximal serum FSH concentrations were reached at 18.19 h for HP-HMG liquid and 15.55 h for HP-hMG powder. In addition to FSH, the PK parameters for hCG were compared between the two HP-hMG formulations. The geometric mean ratios and 90% confidence intervals for HP-hMG liquid versus HP-hMG powder were 0.93 [0.86; 1.01] for AUCt and 0.94 [0.86; 1.02] for Cmax. There was no difference between the two groups in the incidence or severity of adverse events, and both preparations were well tolerated. Mild injection site reactions were less common after administration of HP-hMG liquid by a single injection compared to HP-hMG powder by two injections and were mostly related to pain and erythema after drug administration. Limitations, reasons for caution This bioequivalence study is based on the comparison of single dose administrations in healthy female volunteers of reproductive age. Wider implications of the findings: The new HP-hMG solution for injection in a pre-filled pen will deliver the efficacy and safety of Menopur in a convenient delivery device. Trial registration number NA

Significance of In-Vitro and In-Vivo Correlation in Drug Delivery System

2018 ◽  
Vol 4 (4) ◽  
pp. 523-531
Author(s):  
Hina Mumtaz ◽  
Muhammad Asim Farooq ◽  
Zainab Batool ◽  
Anam Ahsan ◽  
Ashikujaman Syed
Keyword(s):  
Dosage Form ◽  
Pharmaceutical Preparations ◽  
Pharmacokinetic Profile ◽  
In Vitro Dissolution ◽  
Time Saving ◽  
Pharmaceutical Dosage Form ◽  
Short Period ◽  
Form Development

The main purpose of development pharmaceutical dosage form is to find out the in vivo and in vitro behavior of dosage form. This challenge is overcome by implementation of in-vivo and in-vitro correlation. Application of this technique is economical and time saving in dosage form development. It shortens the period of development dosage form as well as improves product quality. IVIVC reduce the experimental study on human because IVIVC involves the in vivo relevant media utilization in vitro specifications. The key goal of IVIVC is to serve as alternate for in vivo bioavailability studies and serve as justification for bio waivers. IVIVC follows the specifications and relevant quality control parameters that lead to improvement in pharmaceutical dosage form development in short period of time. Recently in-vivo in-vitro correlation (IVIVC) has found application to predict the pharmacokinetic behaviour of pharmaceutical preparations. It has emerged as a reliable tool to find the mode of absorption of several dosage forms. It is used to correlate the in-vitro dissolution with in vivo pharmacokinetic profile. IVIVC made use to predict the bioavailability of the drug of particular dosage form. IVIVC is satisfactory for the therapeutic release profile specifications of the formulation. IVIVC model has capability to predict plasma drug concentration from in vitro dissolution media.

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