scholarly journals Effect of Low-Dose Ritonavir on the Pharmacokinetics of the CXCR4 Antagonist AMD070 in Healthy Volunteers

2008 ◽  
Vol 52 (5) ◽  
pp. 1630-1634 ◽  
Author(s):  
Ying Jun Cao ◽  
Charles W. Flexner ◽  
Shelia Dunaway ◽  
Jeong-Gun Park ◽  
Karin Klingman ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Geometric Mean ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Terminal Phase ◽  
Cxcr4 Antagonist ◽  
Time Curve ◽  
Time To Peak ◽  
Immunodeficiency Virus ◽  
Male Subjects

ABSTRACT AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C max), 934 h·ng/ml (313 to 2,127 h·ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC0-∞), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C max of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC0-∞ by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.

scholarly journals Interaction Studies of Tipranavir-Ritonavir with Clarithromycin, Fluconazole, and Rifabutin in Healthy Volunteers

2008 ◽  
Vol 53 (1) ◽  
pp. 162-173 ◽  
Author(s):  
Charles J. L. la Porte ◽  
John P. Sabo ◽  
Mabrouk Elgadi ◽  
D. William Cameron
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Multiple Dose ◽  
Geometric Mean ◽  
Time Curve ◽  
Drug Levels ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
Historical Controls ◽  
Hiv Negative

ABSTRACT Three separate controlled, two-period studies with healthy volunteers assessed the pharmacokinetic interactions between tipranavir-ritonavir (TPV/r) in a 500/200-mg dose and 500 mg of clarithromycin (CLR), 100 mg of fluconazole (FCZ), or 150 mg of rifabutin (RFB). The CLR study was conducted with 24 subjects. The geometric mean ratios (GMR) and 90% confidence intervals (90% CI; given in parentheses) of the areas under the concentration-time curve (AUC), the maximum concentrations of the drugs in serum (C max), and the concentrations in serum at 12 h postdose (Cp12h) for multiple-dose TPV/r and multiple-dose CLR, indicating the effect of TPV/r on the CLR parameters, were 1.19 (1.04-1.37), 0.95 (0.83-1.09), and 1.68 (1.42-1.98), respectively. The formation of the metabolite 14-OH-CLR was decreased by 95% in the presence of TPV, and the TPV AUC increased 66% compared to that for human immunodeficiency virus (HIV)-negative historical controls. The FCZ study was conducted with 20 subjects. The GMR (and 90% CI) of the AUC, C max, and Cp24h, indicating the effect of multiple-dose TPV/r on the multiple-dose FCZ parameters, were 0.92 (0.88-0.95), 0.94 (0.91-0.98), and 0.89 (0.85-0.92), respectively. The TPV AUC increased by 50% compared to that for HIV-negative historical controls. The RFB study was conducted with 24 subjects. The GMR (and 90% CI) of the AUC, C max, and Cp12h for multiple-dose TPV/r and single-dose RFB, indicating the effect of TPV/r on the RFB parameters, were 2.90 (2.59-3.26), 1.70 (1.49-1.94), and 2.14 (1.90-2.41), respectively. The GMR (and 90% CI) of the AUC, C max, and Cp12h of TPV/r and RFB with 25-O-desacetyl-RFB were 4.33 (3.86-4.86), 1.86 (1.63-2.12), and 2.76 (2.44-3.12), respectively. Coadministration of TPV with a single dose of RFB resulted in a 16% increase in the TPV Cp12h compared to that for TPV alone. In the general population, no dose adjustments are necessary for the combination of TPV/r and CLR or FCZ. Combining TPV/r with RFB should be done with caution, while toxicity and RFB drug levels should be monitored. Study medications were generally well-tolerated in these studies.

scholarly journals Safety, toleration, and pharmacokinetics of intravenous azithromycin.

1996 ◽  
Vol 40 (11) ◽  
pp. 2577-2581 ◽  
Author(s):  
D R Luke ◽  
G Foulds ◽  
S F Cohen ◽  
B Levy
Keyword(s):  
Half Life ◽  
Active Drug ◽  
Slow Release ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Concentration Time ◽  
Elimination Half ◽  
The Mean ◽  
Male Subjects

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

scholarly journals Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

2004 ◽  
Vol 48 (11) ◽  
pp. 4328-4331 ◽  
Author(s):  
Robert DiCenzo ◽  
Derick Peterson ◽  
Kim Cruttenden ◽  
Gene Morse ◽  
Garret Riggs ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Valproic Acid ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Blood Samples ◽  
Immunodeficiency Virus ◽  
Before And After ◽  
Trough Concentrations ◽  
Hiv 1

ABSTRACT Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C 0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C 0 and 8-h VPA concentrations versus the control (n = 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n = 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

scholarly journals Effect of Tipranavir-Ritonavir on Pharmacokinetics of Raltegravir

2009 ◽  
Vol 53 (7) ◽  
pp. 2752-2755 ◽  
Author(s):  
William D. Hanley ◽  
Larissa A. Wenning ◽  
Allison Moreau ◽  
James T. Kost ◽  
Eric Mangin ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Study Drug ◽  
Integrase Inhibitor ◽  
Phase Iii ◽  
Open Label ◽  
Time Curve ◽  
Period 2 ◽  
Adverse Experiences ◽  
Immunodeficiency Virus

ABSTRACT Raltegravir (RAL) is a novel and potent human immunodeficiency virus type 1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir (TPV) at 500 mg and ritonavir (RTV) at 200 mg (TPV-RTV) has inhibitory and inductive effects on metabolic enzymes, which includes the potential to induce glucuronosyltransferase. Because RAL may be coadministered with TPV-RTV, there is the potential for the induction of RAL metabolism. Consequently, we assessed the effect of TPV-RTV on the pharmacokinetics of RAL and the safety and tolerability of this combination. Eighteen healthy adults were enrolled in this open-label study. The participants received RAL at 400 mg twice daily for 4 days (period 1) and TPV-RTV twice daily for 7 days (period 2), followed immediately by 400 mg RAL with TPV-RTV twice daily for 4 days (period 3). Under steady-state conditions, the RAL concentration at 12 h (C 12) was decreased when RAL was administered with TPV-RTV (geometric mean ratio [GMR], 0.45; 90% confidence interval [CI] 0.31, 0.66; P = 0.0021); however, the area under the concentration-time curve from time zero to 12 h (GMR, 0.76; 90% CI, 0.49, 1.19; P = 0.2997) and the maximum concentration in serum (GMR, 0.82; 90% CI, 0.46, 1.46; P = 0.5506) were not substantially affected. There were no serious adverse experiences or discontinuations due to study drug-related adverse experiences, and RAL coadministered with TPV-RTV was generally well tolerated. Although the RAL C 12 was decreased with TPV-RTV in this study, favorable efficacy data collected in phase III studies substantiate that TPV-RTV may be coadministered with RAL without dose adjustment.

scholarly journals 81 Bioequivalence of a Manipulation-Resistant Immediate-Release Amphetamine Sulfate Formulation Compared with Reference Standard

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 216-216
Author(s):  
Steve Caras ◽  
Terrilyn Sharpe
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Peak Concentration ◽  
Immediate Release ◽  
Open Label ◽  
Time Curve ◽  
Time To Peak ◽  
Amphetamine Sulfate ◽  
Quantifiable Concentration ◽  
Funding Acknowledgements

AbstractStudy ObjectivesWe compared the bioavailability of racemic amphetamine (d-amphetamine and l-amphetamine) from a manipulation-resistant immediate-release (IR) amphetamine sulfate capsule (AR19) versus amphetamine sulfate IR tablets (reference).MethodIn this open-label, randomized, two-period, two-treatment, two-sequence, crossover study, 36 healthy volunteers aged 18–45 received a single dose (20-mg capsule) of AR19 in one period and a single dose (2 x 10-mg tablets) of reference in another period, after a 10-hour overnight fast. Each drug administration was separated by a washout period of at least 6days. Bioequivalence for d- and l-amphetamine was assessed using time to peak concentration (Tmax), peak concentration in plasma (Cmax), and area under the plasma concentration–time curve from time-zero to the time of the last quantifiable concentration (AUClast) and extrapolated to infinity (AUCinf).ResultsAll 36 volunteers completed both treatment sequences. Mean (standard deviation; SD) Tmax for d- and l-amphetamine was similar for AR19 (2.84[1.05]; 3.05[1.22], respectively) and reference (2.52[0.75]; 2.75[1.00], respectively). The geometric least-squares mean ratios and 90% confidence intervals were within the boundary of 80%–125% for bioequivalence for Cmax (d-amphetamine, 98.35% [96.12–100.64]; l-amphetamine, 98.82% [96.42–101.28]), AUClast (d-amphetamine, 99.45% [96.92–102.05]; l-amphetamine, 99.29% [96.55–102.10]), and AUCinf (d-amphetamine, 99.50%[96.77–102.30]; l-amphetamine, 99.23% [96.06–102.50]). A total of 13 mild adverse events were reported by 7 volunteers (AEs; AR19, n=5; reference, n=8). No serious AEs were reported.ConclusionAR19 was well tolerated and was bioequivalent to reference when administered as a 20-mg dose in healthy volunteers.Funding Acknowledgements: This study was funded by Arbor Pharmaceuticals, LLC.

scholarly journals Didanosine Population Pharmacokinetics in West African Human Immunodeficiency Virus-Infected Children Administered Once-Daily Tablets in Relation to Efficacy after One Year of Treatment

2009 ◽  
Vol 53 (10) ◽  
pp. 4399-4406 ◽  
Author(s):  
Déborah Hirt ◽  
Christophe Bardin ◽  
Serge Diagbouga ◽  
Boubacar Nacro ◽  
Hervé Hien ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Wilcoxon Test ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Drug Concentrations ◽  
Immunodeficiency Virus ◽  
One Year

ABSTRACT Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concentrations, and treatment effects (efficacy/toxicity). Didanosine concentrations were measured for 40 children after 2 weeks and for 9 children after 2 to 5 months of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concentration of the drug in plasma (C max), the area under the concentration-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 months of treatment was evaluated. The threshold AUC that improved efficacy was determined by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and volume of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 months of treatment was significantly correlated with the didanosine AUC and C max (P ≤ 0.02) during the first weeks of treatment. An AUC of >0.60 mg/liter·h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 versus 2.4 log10 copies/ml; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.

scholarly journals Metabolism, Excretion, and Mass Balance of the HIV-1 Integrase Inhibitor Dolutegravir in Humans

2013 ◽  
Vol 57 (8) ◽  
pp. 3536-3546 ◽  
Author(s):  
Stephen Castellino ◽  
Lee Moss ◽  
David Wagner ◽  
Julie Borland ◽  
Ivy Song ◽  
...  
Keyword(s):  
Formation Rate ◽  
Integrase Inhibitor ◽  
Once Daily ◽  
Time To Peak ◽  
Single Oral Administration ◽  
Suspension Formulation ◽  
Immunodeficiency Virus ◽  
Cellular Components ◽  
Male Subjects

ABSTRACTThe pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [14C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t1/2) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.

scholarly journals Pharmacokinetics of Indinavir Combined with Low-Dose Ritonavir in Human Immunodeficiency Virus Type 1-Infected Children

2004 ◽  
Vol 48 (5) ◽  
pp. 1904-1907 ◽  
Author(s):  
A. S. Bergshoeff ◽  
P. L. A. Fraaij ◽  
A. M. C. van Rossum ◽  
G. Verweel ◽  
L. H. Wynne ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Low Dose ◽  
Geometric Mean ◽  
Time Curve ◽  
Minimum Concentration ◽  
Concentration Time ◽  
Immunodeficiency Virus

ABSTRACT So far, no pediatric doses for indinavir combined with ritonavir have been defined. This study evaluated the pharmacokinetics of 400 mg of indinavir/m2 combined with 125 mg of ritonavir/m2 every 12 h (q12h) in 14 human immunodeficiency virus type 1-infected children. The area under the concentration-time curve from 0 to 24 h and the minimum concentration of drug in serum for indinavir were similar to those for 800 mg of indinavir-100 mg of ritonavir q12h in adults, while the maximum concentration of drug in serum was slightly decreased, with geometric mean ratios (90% confidence intervals in parentheses) of 1.1 (0.87 to 1.3), 0.96 (0.60 to 1.5), and 0.80 (0.68 to 0.94), respectively.

scholarly journals A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis Patients

2012 ◽  
Vol 56 (4) ◽  
pp. 2091-2098 ◽  
Author(s):  
Wynand Smythe ◽  
Akash Khandelwal ◽  
Corinne Merle ◽  
Roxana Rustomjee ◽  
Martin Gninafon ◽  
...  
Keyword(s):  
Steady State ◽  
Hiv Infection ◽  
Selection Procedure ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Oral Clearance ◽  
Time Curve ◽  
Turnover Model ◽  
Enzyme Turnover ◽  
Apparent Volume Of Distribution

ABSTRACTThe currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h−1at the first dose, increased 1.82- and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction.

scholarly journals Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Eric Wenzler ◽  
Susan C. Bleasdale ◽  
Monica Sikka ◽  
Kristen L. Bunnell ◽  
Matthew Finnemeyer ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Adult ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Open Label ◽  
Time Curve ◽  
Elimination Half ◽  
Apparent Clearance ◽  
Dosing Regimens ◽  
Repeated Dosing

ABSTRACTThe pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n= 11) and urine (n= 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 μg/ml, time toCmax(Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) = 151.6 ± 35.6 versus 156.6 ± 42.5 μg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 μg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%;P< 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.)

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