Clofazimine pharmacokinetics in patients with TB: dosing implications

Abstract Background Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. Objectives To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Patients and methods Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. Results We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Conclusions Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

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Optimization of Personalized Amlodipine Dosing Strategies for Children Based on Pharmacokinetic Data from Chinese Male Adults and PBPK Modeling

Children ◽

10.3390/children8110950 ◽

2021 ◽

Vol 8 (11) ◽

pp. 950

Author(s):

Xiaolu Han ◽

Xiaoxuan Hong ◽

Xianfu Li ◽

Yuxi Wang ◽

Zengming Wang ◽

...

Keyword(s):

Pbpk Model ◽

Plasma Concentrations ◽

Pbpk Modeling ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Optimal Dosage ◽

Continuous Administration ◽

Dosing Strategies ◽

Chinese Male ◽

Enzyme Metabolism

For children, a special population who are continuously developing, a reasonable dosing strategy is the key to clinical therapy. Accurate dose predictions can help maximize efficacy and minimize pain in pediatrics. Methods: This study collected amlodipine pharmacokinetics (PK) data from 236 Chinese male adults and established a physiological pharmacokinetic (PBPK) model for adults using GastroPlus™. A PBPK model of pediatrics is constructed based on hepatic-to-body size and enzyme metabolism, used similar to the AUC0-∞ to deduce the optimal dosage of amlodipine for children aged 1–16 years. A curve of continuous administration for 2-, 6-, 12-, 16-, and 25-year-olds and a personalized administration program for 6-year-olds were developed. Results: The results show that children could not establish uniform allometric amplification rules. The optimal doses were 0.10 mg·kg−1 for ages 2–6 years and −0.0028 × Age + 0.1148 (mg/kg) for ages 7–16 years, r = 0.9941. The trend for continuous administration was consistent among different groups. In a 6-year-old child, a maintenance dose of 2.30 mg was used to increase the initial dose by 2.00 mg and the treatment dose by 1.00 mg to maintain stable plasma concentrations. Conclusions: A PBPK model based on enzyme metabolism can accurately predict the changes in the pharmacokinetic parameters of amlodipine in pediatrics. It can be used to support the optimization of clinical treatment plans in pediatrics.

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Serum bactericidal activities and comparative pharmacokinetics of meropenem and imipenem-cilastatin.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.1.105 ◽

1996 ◽

Vol 40 (1) ◽

pp. 105-109 ◽

Cited By ~ 48

Author(s):

M Dreetz ◽

J Hamacher ◽

J Eller ◽

K Borner ◽

P Koeppe ◽

...

Keyword(s):

Compartment Model ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Dose Administration ◽

Microdilution Method ◽

Two Compartment Model ◽

Elimination Half ◽

Renal Clearances ◽

The Mean ◽

Bactericidal Activities

The pharmacokinetics and serum bactericidal activities (SBAs) of imipenem and meropenem were investigated in a randomized crossover study. Twelve healthy male volunteers received a constant 30-min infusion of either 1 g of imipenem plus 1 g of cilastatin or 1 g of meropenem. The concentrations of the drugs in serum and urine were determined by bioassay and high-pressure liquid chromatography. Pharmacokinetic parameters were based on an open two-compartment model and a noncompartmental technique. At the end of infusion, the mean concentrations of imipenem and meropenem measured in serum were 61.2 +/- 9.8 and 51.6 +/- 6.5 mg/liter, respectively; urinary recoveries were 48.6% +/- 8.2% and 60.0% +/- 6.5% of the dose in 12 h, respectively; and the areas under the concentration-time curve from time zero to infinity were 96.1 +/- 14.4 and 70.5 +/- 10.3 mg.h/liter, respectively (P < or = 0.02). Imipenem had a mean half-life of 66.7 +/- 10.4 min; that of meropenem was 64.4 +/- 6.9 min. The volumes of distribution at steady state of imipenem and meropenem were 15.3 +/- 3.3 and 18.6 +/- 3.0 liters/70 kg, respectively, and the mean renal clearances per 1.73 m2 were 85.6 +/- 17.6 and 144.6 +/- 26.0 ml/min, respectively. Both antibiotics were well tolerated in this single-dose administration study. The SBAs were measured by the microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. Mean reciprocal bactericidal titers were measured 1 and 6 h after administration. After 1 and 6 h the median SBAs for imipenem and meropenem, were 409 and 34.9 and 97.9 and 5.8, respectively, against Staphylococcus aureus, 19.9 and 4.4 and 19.4 and 4.8, respectively, against Pseudomonas aeruginosa, 34.3 and 2.2 and 232 and 15.5, respectively, against Enterobacter cloacae, and 13.4 and 2.25 and 90.7 and 7.9, respectively, against Proteus mirabilis. Both drugs had rather short biological elimination half-lives and a predominantly renal route of elimination. Both carbapenems revealed high SBAs against clinically important pathogens at 1 h; meropenem had a higher SBA against E. cloacae and P. mirabilis, and the SBA of imipenem against S. aureus was greater than the SBA of meropenem.

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Pharmacodynamics of a Long-Acting Echinocandin, CD101, in a Neutropenic Invasive-Candidiasis Murine Model Using an Extended-Interval Dosing Design

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02154-17 ◽

2017 ◽

Vol 62 (2) ◽

Cited By ~ 17

Author(s):

Alexander J. Lepak ◽

Miao Zhao ◽

Brian VanScoy ◽

Paul G. Ambrose ◽

David R. Andes

Keyword(s):

Invasive Candidiasis ◽

Half Life ◽

Intraperitoneal Administration ◽

Time Curve ◽

Content Type ◽

Elimination Half ◽

Dosing Regimens ◽

Dosing Strategies ◽

Long Acting

ABSTRACT Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans, making it possible to design once-weekly dosing strategies. The present study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select Candida albicans (n = 4), C. glabrata (n = 3), and C. parapsilosis (n = 3) strains. The CD101 MIC ranged from 0.03 to 1 mg/liter. Plasma pharmacokinetic measurements were performed using uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 to 41 h. Neutropenic mice were infected with each strain by lateral tail vein injection, treated with a single dose of CD101, and monitored for 7 days, at which time the organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC index) correlated well with efficacy (R 2, 0.74 to 0.93). The median stasis 24-h free-drug AUC/MIC targets were as follows: for C. albicans, 2.92; for C. glabrata, 0.07; and for C. parapsilosis, 2.61. The PK/PD targets for 1-log10 kill endpoint were 2- to 4-fold higher. Interestingly, the aforementioned PK/PD targets of CD101 were numerically lower for all three species than those of other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent in vivo pharmacodynamic activity.

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

Animals ◽

10.3390/ani8080142 ◽

2018 ◽

Vol 8 (8) ◽

pp. 142

Author(s):

Dinakaran Venkatachalam ◽

Paul Chambers ◽

Kavitha Kongara ◽

Preet Singh

Keyword(s):

Total Dose ◽

Plasma Concentrations ◽

Subcutaneous Administration ◽

Lidocaine Hydrochloride ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Studies ◽

Liquid Chromatography Mass Spectrometry ◽

Elimination Half ◽

The Mean ◽

Safe Dose

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

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Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05710-11 ◽

2011 ◽

Vol 56 (1) ◽

pp. 70-74 ◽

Cited By ~ 32

Author(s):

Paul M. Beringer ◽

Heather Owens ◽

Albert Nguyen ◽

Debbie Benitez ◽

Adupa Rao ◽

...

Keyword(s):

Cystic Fibrosis ◽

Oral Administration ◽

Maximum Concentration ◽

Airway Remodeling ◽

Plasma Concentrations ◽

Compartment Model ◽

Time Curve ◽

Elimination Half ◽

Dose Oral

ABSTRACTCystic fibrosis (CF) is characterized by a chronic neutrophilic inflammatory response resulting in airway remodeling and progressive loss of lung function. Doxycycline is a tetracycline antibiotic that inhibits matrix metalloproteinase 9, a protease known to be associated with the severity of lung disease in CF. The pharmacokinetics of doxycycline was investigated during the course of a clinical trial to evaluate the short-term efficacy and safety in adults with CF. Plasma samples were obtained from 14 patients following a single intravenous dose and after 2 and 4 weeks of oral administration of doses ranging from 40 to 200 mg daily. The data were analyzed using noncompartmental and compartmental pharmacokinetics. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-∞) values ranged from 1.0 to 3.16 mg/liter and 15.2 to 47.8 mg/liter × h, respectively, following single intravenous doses of 40 to 200 mg.Cmaxand time to maximum concentration of drug in serum (Tmax) values following multiple-dose oral administration ranged from 1.15 to 3.04 mg/liter and 1.50 to 2.33 h, respectively, on day 14 and 1.48 to 3.57 mg/liter and 1.00 to 2.17 on day 28. Predose sputum/plasma concentration ratios on days 14 and 28 ranged from 0.33 to 1.1 (mean, 0.71 ± 0.33), indicating moderate pulmonary penetration. A 2-compartment model best described the combined intravenous and oral data. Absorption was slow and delayed (absorption rate constant [Ka], 0.414 h−1; lag time, 0.484 h) but complete (bioavailability [F], 1.16). The distribution and elimination half-lives were 0.557 and 18.1 h, respectively. Based on these data, the plasma concentrations at the highest dose, 200 mg/day, are in the range reported to produce anti-inflammatory effectsin vivoand should be evaluated in clinical trials.

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Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

Pharmaceutics ◽

10.3390/pharmaceutics11110566 ◽

2019 ◽

Vol 11 (11) ◽

pp. 566 ◽

Cited By ~ 2

Author(s):

Yoann Cazaubon ◽

Yohann Talineau ◽

Catherine Feliu ◽

Céline Konecki ◽

Jennifer Russello ◽

...

Keyword(s):

Adrenocortical Carcinoma ◽

Plasma Concentrations ◽

Therapeutic Index ◽

Compartment Model ◽

Volume Of Distribution ◽

Pharmacokinetic Analysis ◽

Concentration Data ◽

Starting Dose ◽

Dosing Regimens ◽

Data Files

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2–3 g/day and should be slightly increased to reach the therapeutic index of 14–20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h−1 (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.

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Pharmacokinetic Evaluation of anti-HIV Drug Interactions: Effect of Zidovudine on 2′-3′-Dideoxyinosine Kinetics in Monkeys

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029300400304 ◽

1993 ◽

Vol 4 (3) ◽

pp. 155-159 ◽

Cited By ~ 2

Author(s):

M. Qian ◽

A. R. Swagler ◽

M. Mehta ◽

C.T. Vishwanathan ◽

J. M. Gallo

Keyword(s):

Dose Group ◽

Plasma Concentrations ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

High Dose ◽

Combination Regimen ◽

Time Profiles ◽

Elimination Half ◽

Constant Rate ◽

Rate Infusion

The current investigation was conducted to determine if zidovudine (AZT) altered the pharmacokinetics of dideoxyinosine (ddl) in non-hurnan primates, an appropriate animal model for AZT and ddl pharmacokinetics in human. Each of nine animals received 20 mg kg−1 of ddl intravenously in the absence and presence of two different dosage regimens of AZT. For each combination regimen, AZT was administered as a combined i.v. bolus-constant rate infusion regimen for 30 min that produced AZT plasma concentrations of about 4 μg ml−1 in six animals (low dose group) and 11 μg ml−1 in three others (high dose group). Serial blood samples were collected, and pharmacokinetic parameters for ddl were calculated based on plasma ddl concentrations measured by HPLC techniques. The pharmacokinetics of ddl given alone in the first phase of the low ( n = 6) and high ( n = 6) dose AZT groups, resulted in a mean elimination half-life 1.54 and 1.9h, a mean total clearance of 0.62 and 0.731 h−1 kg−1, and a mean steady state volume of distribution of 1.02 and 0.891 kg−1, respectively. Following combined ddl and AZT administrations, in both the low and high dose AZT groups, plasma concentration-time profiles of ddl were similar for each monkey, and no statistical differences were observed in the pharmacokinetic parameters compared to those obtained when ddl was given alone. The fact that AZT does not alter the pharmacokinetics of ddl at the range of AZT dose studied provides a basis for rational dosage design for combined ddl and AZT treatments in HIV infection.

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CHARACTERIZATION OF PHARMACOKINETICS OF 2-((3-(CHLOROMETHYL)BENZOYL)OXY) BENZOIC ACID IN RATS BY USING HPLC-DAD METHOD

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2019v11i5.34536 ◽

2019 ◽

pp. 279-283

Author(s):

Caroline ◽

Nathania Sie ◽

Kuncoro Foe ◽

Senny Yesery Esar ◽

Maria Anabella Jessica

Keyword(s):

Benzoic Acid ◽

Oral Administration ◽

Plasma Concentrations ◽

Compartment Model ◽

The Body ◽

Pharmacokinetic Parameters ◽

Log P ◽

Potential Candidate ◽

Onset Of Action ◽

Fasting Period

Objective: A new compound of salicylic acid derivative, namely 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid (3CBB), was synthesized to find a compound exhibiting higher analgesic activity and smaller ulcer irritation than acetylsalicylic acid (ASA). Therefore, this study aimed to investigate the pharmacokinetics of this new compound in rats, following a single dose oral administration of 3CBB (45 mg/kg BW). Methods: Plasma samples of 9 healthy rats were collected before and up to 3 h after its oral administration, following an 18 h fasting period. Plasma concentrations of 3CBB were determined using a validated HPLC-DAD assay. Pharmacokinetic parameters were determined using the compartment model technique. All experiments were carried out in triplicate. Results: The pharmacokinetic parameters of 3CBB obtained were as follows: Tmax= 28.9±1.1 min, Cmax = 0.57±0.02 µg/ml, AUCtotal = 66.3±1.0 µg min/ml, Kel = 0.018±0.002 min-1, and T1/2el = 39.4±3.9 min. The long elimination half-life and low Cmax indicated that 3CBB was extensively distributed in the deep and very deep tissues. This confirmed the unique and special characteristics of a highly lipophilic compound like 3CBB (log P = 3.73). Conclusion: 3CBB demonstrated a slower onset of action and longer elimination time from the body compared to ASA. Thus this new compound is a potential candidate to be developed as a new drug.

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Pharmacokinetic Data Are Predictive ofIn VivoEfficacy for Cefixime and Ceftriaxone against Susceptible and ResistantNeisseria gonorrhoeaeStrains in the Gonorrhea Mouse Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01644-18 ◽

2019 ◽

Vol 63 (3) ◽

Cited By ~ 9

Author(s):

Kristie L. Connolly ◽

Ann E. Eakin ◽

Carolina Gomez ◽

Blaire L. Osborn ◽

Magnus Unemo ◽

...

Keyword(s):

Single Dose ◽

Mouse Model ◽

Infection Model ◽

Pharmacokinetic Data ◽

Drug Resistant ◽

Genital Tract Infection ◽

Clear Dose Response ◽

Dosing Regimens ◽

Strain Fa1090

ABSTRACTThere is a pressing need for drug development for gonorrhea. Here we describe a pharmacokinetic (PK)/pharmacodynamic (PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. The PK determined in uninfected mice displayed a clear dose-response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESC-susceptible (ESCs) strain FA1090 were 5 mg/kg of body weight (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (the time that the free drug concentration remains above the MIC [fTMIC]) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against ESC-resistant (ESCr) strain H041. However, fractionation (three times a day every 8 h [TIDq8h]) of a 120-mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to the findings for gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤50% of mice, with the therapeutic times estimated from single-dose PK data being 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships observed in mice reflected those observed in humans, within vivoefficacy against an ESCsstrain requiring doses that yielded anfTMICin excess of 20 to 24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCrstrain and were useful in designing effective dosing regimens.

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Pharmacokinetics of Different Dosing Strategies of Oral Posaconazole in Patients with Compromised Gastrointestinal Function and Who Are at High Risk for Invasive Fungal Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05937-11 ◽

2012 ◽

Vol 56 (5) ◽

pp. 2652-2658 ◽

Cited By ~ 32

Author(s):

Oliver A. Cornely ◽

David Helfgott ◽

Amelia Langston ◽

Werner Heinz ◽

Jörg-Janne Vehreschild ◽

...

Keyword(s):

Steady State ◽

High Risk ◽

Fungal Infections ◽

Plasma Concentrations ◽

Nutritional Supplement ◽

Gastrointestinal Function ◽

Open Label ◽

Dosing Regimens ◽

Dosing Strategies ◽

Poor Absorption

ABSTRACTThe aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these “poor absorbers” on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification.

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