scholarly journals A single-arm study to evaluate the transfer of drospirenone to breast milk after reaching steady state, following oral administration of 4 mg drospirenone in healthy lactating female volunteers

2020 ◽  
Vol 16 ◽  
pp. 174550652095719
Author(s):  
Dace Melka ◽  
Kalev Kask ◽  
Enrico Colli ◽  
Pedro-Antonio Regidor
Keyword(s):  
Steady State ◽  
Breast Milk ◽  
Area Under The Curve ◽  
Average Concentration ◽  
Primary Objective ◽  
Repeated Dose ◽  
Open Label ◽  
Time Curve ◽  
Dose Administration ◽  
Concentration Time

Objective: The primary objective of this trial was to assess the transfer of drospirenone to breast milk after daily administration of an oral test preparation containing 4 mg of drospirenone at the steady state. The secondary objective of the trial was to assess safety based on clinical and laboratory measurements and reporting of adverse events and/or adverse drug reactions. Patients and Methods: This was an open label, non-comparative single-center study. Drospirenone 4 mg per day was the first postpartum contraceptive for the study participants who were no longer breastfeeding yet were still lactating. It was administered for 7 days to achieve steady-state concentration. All participants were volunteers who planned to use oral contraceptives as their family planning method in the future. Results: Twelve volunteers completed the trial according to the protocol, and the samples of all 12 study completers were analyzed. The average concentration–time curve of drospirenone in plasma 24 h after the administration of the last dose (area under the curve (0–24 h)) was 635.33 ng h/mL and 120 h after the single repeated dose administration (area under the curve (0–120 h)) was 1180.57 ng h/mL, respectively. The average Cmax was 48.64 ng/mL. The average concentration–time curve of drospirenone in milk 24 h after the administration of the last dose (area under the curve (0–24 h)) was 134.35 ng h/mL and 120 h after the single repeated dose administration (area under the curve (0–120 h)) was 227.17 ng h/mL, respectively. The average Cmax was 10.34 ng/mL. Conclusion: On average, 18.13% of plasma drospirenone made it to breast milk and the highest concentration of drospirenone in breast milk was 17.55% of that in plasma. The total quantity of drospirenone passing to breast milk is on average 4478 ng during a 24-h period representing 0.11% of the maternal daily dose. Thus, at the recommended doses, no effects on breastfed newborns/infants are anticipated with drospirenone 4 mg.

scholarly journals A Single Arm Study to Evaluate the Transfer of Drospirenone to Breast Milk after Reaching Steady State after Oral Administration of 4 MG Drospirenone Only Pill in Healthy Lactating Female Volunteers

2020 ◽  
Author(s):  
Dace Melka ◽  
Kalev Kask ◽  
Enrico Colli ◽  
Pedro-Antonio Regidor
Keyword(s):  
Steady State ◽  
Breast Milk ◽  
Average Concentration ◽  
Primary Objective ◽  
Repeat Dose ◽  
Open Label ◽  
Time Curve ◽  
Dose Administration ◽  
Concentration Time ◽  
Study Participants

Objective: The primary objective of this trial was to assess the transfer of drospirenone to breast milk after daily administration of an oral test preparation containing 4 mg of drospirenone at the steady state. The secondary objective of the trial was to assess the safety of the preparation based on safety clinical and laboratory measurements (at the beginning and at the end of the trial) and reporting of adverse events and/or adverse drug reactions. Patients and Methods: This was an open label, non-comparative single center study. Drospirenone 4mg per day was the first postpartum contraceptive for the study participants who were no longer breastfeeding yet were still lactating. It was administered for 7 (seven) days to achieve steady-state concentration. All participants were volunteers who planned to use oral contraceptives as their family planning method in the future. Results: A total number of 12 volunteers completed the trial according to the protocol and the samples of all the 12 study completers were analyzed. The average concentration-time curve of drospirenone in plasma 24 h after the administration of the last dose (AUC(0-24h)) was 635.33 ng*h/mL and 120 h after the single repeat dose administration (AUC(0-120h) was 1180.57 ng*h/mL, respectively. The average Cmax was 48.64 ng/mL. The average concentration-time curve of drospirenone in milk 24 h after the administration of the last dose (AUC(0-24h)) was 134.35 ng*h/mL and 120 h after the single repeat dose administration (AUC(0-120h) was 227.17 ng*h/mL respectively. The average Cmax was 10.34 ng/mL. Conclusion: On average 18.13% of plasma drospirenone made it to breast milk and the highest concentration of drospirenone in breast milk was 17.55% of that in plasma. The total quantity of drospirenone passing to breast milk is on average 4478 ng during a 24 h period representing 0.11% of the maternal daily dose. Thus, at the recommended doses, no effects on breastfed newborns/infants are anticipated with drospirenone 4 mg.

scholarly journals Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

2007 ◽  
Vol 51 (8) ◽  
pp. 2982-2984 ◽  
Author(s):  
Mary B. Wire ◽  
Charles H. Ballow ◽  
Julie Borland ◽  
Mark J. Shelton ◽  
Yu Lou ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Open Label Study ◽  
Label Study ◽  
Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

scholarly journals Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

1999 ◽  
Vol 43 (5) ◽  
pp. 1152-1155 ◽  
Author(s):  
Kevin W. Garey ◽  
Charles A. Peloquin ◽  
Paul G. Godo ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Steady State Concentration ◽  
Open Label ◽  
Time Curve ◽  
Data Analyses ◽  
Concentration Time ◽  
State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

scholarly journals Oral Repeated-Dose Toxicity Studies of Coenzyme Q10 in Beagle Dogs

2012 ◽  
Vol 31 (1) ◽  
pp. 58-69 ◽  
Author(s):  
Padmaja Yerramilli-Rao ◽  
M. Flint Beal ◽  
Dai Watanabe ◽  
Karl Kieburtz ◽  
Elisabeth A. de Blieck ◽  
...  
Keyword(s):  
Steady State ◽  
Coenzyme Q10 ◽  
Area Under The Curve ◽  
Phase Iii ◽  
Repeated Dose ◽  
Beagle Dogs ◽  
Time Curve ◽  
Repeated Dose Toxicity ◽  
Dose Study ◽  
Support Phase

To support phase III testing of coenzyme Q10 (CoQ10) in humans, we conducted pharmacokinetic and toxicology studies in beagle dogs. Following single gavage administration of CoQ10 at 600, 1200, 1800, or 2400 mg/kg per d no obvious dose response was observed in maximum concentration ( Cmax) or area under the curve (AUC) versus time curve at the 3 highest dosages. In a repeated-dose study of CoQ10 at 600, 1200, 1800, or 2400 mg/kg per d for 4 weeks, CoQ10 reached steady state in plasma by 2 weeks at all dosages. Both Cmax and AUC increased with increasing dosage of CoQ10. The highest plasma levels were recorded at 1800 mg/kg per d. In a 39-week chronic toxicity study of CoQ10 at 1200 and 1800 mg/kg per d or placebo, CoQ10 reached steady state in plasma by 13 weeks. Behaviors, blood chemistries, and detailed histopathology were normal. No deaths occurred. These results support the use of a 2400 mg/d dosage of CoQ10 in human clinical trials.

scholarly journals Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Julian Lindsay ◽  
Stuart Mudge ◽  
George R. Thompson
Keyword(s):  
Steady State ◽  
Maximum Concentration ◽  
Healthy Adults ◽  
Plasma Exposure ◽  
Open Label ◽  
Time Curve ◽  
Dosing Interval ◽  
Fasted State ◽  
Concentration Time ◽  
Bioavailability Study

ABSTRACT To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled super bioavailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P = 0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P = 0.0083).

scholarly journals Differential Effects of Tipranavir plus Ritonavir on Atorvastatin or Rosuvastatin Pharmacokinetics in Healthy Volunteers

2009 ◽  
Vol 53 (10) ◽  
pp. 4385-4392 ◽  
Author(s):  
P. A. Pham ◽  
C. J. L. la Porte ◽  
L. S. Lee ◽  
R. van Heeswijk ◽  
J. P. Sabo ◽  
...  
Keyword(s):  
Single Dose ◽  
Steady State ◽  
Adverse Events ◽  
Confidence Interval ◽  
Geometric Mean ◽  
Drug Reactions ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time ◽  
Gastrointestinal Intolerance

ABSTRACT To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (C max) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the C max of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r.

scholarly journals Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials

2011 ◽  
Vol 55 (5) ◽  
pp. 2290-2296 ◽  
Author(s):  
Thomas N. Kakuda ◽  
Samantha Abel ◽  
John Davis ◽  
Julia Hamlin ◽  
Monika Schöller-Gyüre ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Volunteers ◽  
Potent Inhibitor ◽  
Cytochrome P450 3A ◽  
Short Term ◽  
Two Phase ◽  
Time Curve ◽  
Safety Issues ◽  
Concentration Time ◽  
Crossover Studies

ABSTRACTThe effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC123.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine.

scholarly journals Pharmacokinetic Interactions between the Hormonal Emergency Contraception, Levonorgestrel (Plan B), and Efavirenz

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Monica L. Carten ◽  
Jennifer J. Kiser ◽  
Awewura Kwara ◽  
Samantha Mawhinney ◽  
Susan Cu-Uvin
Keyword(s):  
Geometric Mean ◽  
Liver Function Tests ◽  
Open Label ◽  
Time Curve ◽  
Geometric Means ◽  
Concentration Time ◽  
Plan B ◽  
Effective Contraception ◽  
Grade 3 ◽  
Hiv Negative

Objectives. Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC12) prior to and with efavirenz (EFV).Design. Prospective, open-label, single-arm, equivalence study.Methods. Healthy HIV-negative subjects underwent 12 hr intensive pharmacokinetic (PK) sampling following single dose LNG alone and after 14 days of EFV. Geometric means, Geometric Mean Ratios, and 90% confidence intervals (CI) are reported for PK Parameters.T-tests were utilized. Clinical parameters and liver function tests (LFTs) were assessed.Results. 24 women enrolled and 21 completed the study. With EFV, LNG AUC12was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng*hr/mL, and maximum concentration (Cmax⁡) was reduced 41% (95% CI: 33%, 50%) from 8.4 to 4.6 ng/mL. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities.Conclusions. EFV significantly reduced LNG exposures. Higher LNG doses may be required with EFV. These results reinforce the importance of effective contraception in women taking EFV.

scholarly journals Lack of Effect of Simultaneously Administered Didanosine Encapsulated Enteric Bead Formulation (Videx EC) on Oral Absorption of Indinavir, Ketoconazole, or Ciprofloxacin

2002 ◽  
Vol 46 (2) ◽  
pp. 385-391 ◽  
Author(s):  
Bharat D. Damle ◽  
Vanaja Mummaneni ◽  
Sanjeev Kaul ◽  
Catherine Knupp
Keyword(s):  
Oral Absorption ◽  
Historical Data ◽  
Point Estimate ◽  
Open Label ◽  
Time Curve ◽  
Geometric Means ◽  
Point Estimates ◽  
Concentration Time ◽  
Crossover Studies ◽  
Post Hoc

ABSTRACT Didanosine formulation that contains a buffer to prevent it from acid-mediated degradation can result in a significant decrease in the oral absorption of certain drugs because of interactions with antacids. An enteric formulation of didanosine is unlikely to cause such drug interactions because it lacks antacids. This study was undertaken to determine whether the enteric bead formulation of didanosine (Videx EC) influences the bioavailability of indinavir, ketoconazole, and ciprofloxacin, three drugs that are representative of a broader class of drugs affected by interaction with antacids. Healthy subjects of either gender were enrolled in three separate open-label, single-dose, two-way crossover studies. Subjects were randomized to treatment A (800 mg of indinavir, 200 mg of ketoconazole, or 750 mg of ciprofloxacin) or treatment B (same dose of indinavir, ketoconazole, or ciprofloxacin, but with 400 mg of didanosine as an encapsulated enteric bead formulation). A lack of interaction was concluded if the 90% confidence interval (CI) of the ratio of the geometric means of log-transformed C max and AUC0-∞ values (i.e., values for the area under the concentration-time curve from time zero to infinity) of indinavir, ketoconazole, and ciprofloxacin were contained entirely between 0.75 and 1.33. For indinavir (n = 23), the point estimate (90% CI; minimum, maximum) of the ratios of C max and AUC0-∞ values were 0.99 (0.91, 1.06) and 0.96 (0.91, 1.02), respectively. In the ketoconazole study, 3 of 24 subjects showed anomalous absorption of ketoconazole (i.e., an ∼8-fold-lower AUC compared to historical data), which was the reference treatment. A post hoc analysis performed after these three subjects were excluded indicated that the point estimates (90% CI) of the ratios of Cmax and AUC0-∞ values were 0.99 (0.86, 1.14) and 0.97 (0.85, 1.10), respectively. For ciprofloxacin (n = 16), the point estimate (90% CI) of the ratios of C max and AUC0-∞ values were 0.92 (0.79, 1.07) and 0.91 (0.76, 1.08), respectively. All three studies clearly indicated a lack of interaction. The T max and t 1/2 for indinavir, ketoconazole, and ciprofloxacin were similar between treatments. Our results showed that the lack of interaction of didanosine encapsulated enteric bead formulation with indinavir, ketoconazole, and ciprofloxacin indicates that this enteric formulation of didanosine can be concomitantly administered with drugs whose bioavailability is known to be reduced by interaction with antacids.

scholarly journals Pharmacokinetics of Telavancin at Fixed Doses in Normal-Body-Weight and Obese (Classes I, II, and III) Adult Subjects

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Kristen L. Bunnell ◽  
Manjunath P. Pai ◽  
Monica Sikka ◽  
Susan C. Bleasdale ◽  
Eric Wenzler ◽  
...  
Keyword(s):  
Body Weight ◽  
Time Profile ◽  
Primary Objective ◽  
Fixed Dose ◽  
Target Area ◽  
Obese Patients ◽  
Time Curve ◽  
Content Type ◽  
Time Zero ◽  
Concentration Time

ABSTRACT A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects ( n = 32) received a single, weight-stratified, fixed dose of 500 mg ( n = 4), 750 mg ( n = 8), or 1,000 mg ( n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m 2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m 2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC 0–∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.)

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