Effect of diabetes mellitus on TB drug concentrations in Tanzanian patients

Abstract Background Diabetes mellitus (DM) is associated with poor TB treatment outcome. Previous studies examining the effect of DM on TB drug concentrations yielded conflicting results. No studies have been conducted to date in an African population. Objectives To compare exposure to TB drugs in Tanzanian TB patients with and without DM. Patients and methods A prospective pharmacokinetic study was performed among 20 diabetic and 20 non-diabetic Tanzanian TB patients during the intensive phase of TB treatment. Plasma pharmacokinetic parameters of isoniazid, rifampicin, pyrazinamide and ethambutol were compared using an independent-sample t-test on log-transformed data. Multiple linear regression analysis was performed to assess the effects of DM, gender, age, weight, HIV status and acetylator status on exposure to TB drugs. Results A trend was shown for 25% lower total exposure (AUC0–24) to rifampicin among diabetics versus non-diabetics (29.9 versus 39.9 mg·h/L, P=0.052). The AUC0–24 and peak concentration (Cmax) of isoniazid were also lower in diabetic TB patients (5.4 versus 10.6 mg·h/L, P=0.015 and 1.6 versus 2.8 mg/L, P=0.013). Pyrazinamide AUC0–24 and Cmax values were non-significantly lower among diabetics (P=0.08 and 0.09). In multivariate analyses, DM remained an independent predictor of exposure to isoniazid and rifampicin, next to acetylator status for isoniazid. Conclusions There is a need for individualized dosing of isoniazid and rifampicin based on plasma concentration measurements (therapeutic drug monitoring) and for clinical trials on higher doses of these TB drugs in patients with TB and DM.

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Optimum Use of Therapeutic Drug Monitoring and Pharmacokinetics-Pharmacodynamics in the NICU

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-14.2.66 ◽

2009 ◽

Vol 14 (2) ◽

pp. 66-74

Author(s):

Peter Gal

Keyword(s):

Drug Therapy ◽

Therapeutic Drug Monitoring ◽

Antiepileptic Drugs ◽

Therapeutic Range ◽

Drug Monitoring ◽

Population Based ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Patient Response ◽

Drug Concentrations

Therapeutic drug monitoring is increasingly giving way to dosing drugs based on population-based pharmacokinetic parameters, even when pharmacokinetic values vary quite a bit in individual patients. Further, drug concentrations are often considered appropriate if they are within a defined therapeutic range, even if the patient response is suboptimal. This lecture discusses the limitations of therapeutic ranges in neonates, and proposes greater emphasis on pharmacodynamic curves to individualize drug therapy. Examples are provided using methylxanthines, indomethacin, antiepileptic drugs and aminoglycosides. The potential to use pharmacokinetic findings to describe physiologic changes and occasionally assist with diagnosis is also discussed.

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Comparison of two empirical prolonged infusion dosing regimens for meropenem in patients with septic shock: A pilot two-center study

10.21203/rs.3.rs-48494/v1 ◽

2020 ◽

Author(s):

Albrecht Eisert ◽

Christian Lanckohr ◽

Janina Frey ◽

Otto Frey ◽

Sebastian G. Wicha ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Severe Disease ◽

Therapeutic Drug ◽

Prolonged Infusion ◽

Minimal Inhibitory Concentrations ◽

Drug Concentrations ◽

Dosing Regimens ◽

Higher Doses ◽

Extended Infusion

Abstract Background : Sepsis is a severe disease with complex pathophysiology and high mortality. Meropenem is frequently used in sepsis to treat the underlying infection. Studies have shown that standard doses of meropenem are frequently inadequate due to high pharmacokinetic and pharmacodynamic variability. Therapeutic drug monitoring (TDM) of meropenem is not widely available, and increased empiric dosing recommendations are needed. Methods : We compared two empiric dosing schemes of meropenem using extended infusion (120 minutes) in 32 patients with sepsis in the ICUs at two different hospitals. One regimen was 3x 2 g meropenem/ 24 h for two days, followed by 3x 1 g meropenem/ 24 h; the other regimen was 4x 1 g meropenem/ 24 h. Serum meropenem concentrations were measured for the first 72 h of therapy, and pharmacokinetic modelling was performed to define the percentage of time the dosing interval was above various target minimal inhibitory concentrations (MICs) for each regimen (%fT >MIC ). Results : Both regimens led to a sufficiently high %fT >MIC for pathogens with target MICs below 4 mg/L. When higher MICs were targeted, the %fT >MIC of 4x 1 g meropenem decreased faster than that of 3x 2 g meropenem. At high MICs of 32 mg/L, both dosing regimens failed to provide drug concentrations deemed appropriate for clinical improvement. Conclusions : The results of this pilot study can guide clinicians in their choice of an empirical dosing scheme when prescribing meropenem in the absence of TDM. If pathogens with low MICs (<4 mg/L) are targeted, both dosing regimens are adequate, whereas more resistant clones require higher doses. The control of β-lactam therapy by therapeutic drug monitoring is desirable.

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Early Therapeutic Drug Monitoring for Isoniazid and Rifampin among Diabetics with Newly Diagnosed Tuberculosis in Virginia, USA

Tuberculosis Research and Treatment ◽

10.1155/2013/129723 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 9

Author(s):

Scott K. Heysell ◽

Jane L. Moore ◽

Debbie Staley ◽

Denise Dodge ◽

Eric R. Houpt

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Prolonged Treatment ◽

Therapeutic Drug ◽

Diabetic Patients ◽

Newly Diagnosed ◽

Tb Treatment ◽

A Value ◽

Drug Concentrations

Slow responders to tuberculosis (TB) treatment in Virginia have prolonged treatment duration and consume more programmatic resources. Diabetes is an independent risk factor for slow response and low serum anti-TB drug concentrations. Thus, a statewide initiative of early therapeutic drug monitoring (TDM) for isoniazid and rifampin at 2 weeks after TB treatment was piloted for all diabetics with newly diagnosed TB. During the period of early TDM, 12/01/2011–12/31/2012, 21 diabetics hadC2 hrconcentrations performed and 16 (76%) had a value below the expected range for isoniazid, rifampin, or both. Fifteen had follow-up concentrations after dose adjustment and 12 (80%) increased to within the expected range (including all for rifampin). Of 16 diabetic patients with pulmonary TB that had early TDM, 14 (88%) converted their sputum culture to negative in <2 months. Early TDM for diabetics was operationally feasible, may speed response to TB therapy, and can be considered for TB programs with high diabetes prevalence.

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Effect of CYP3A5 Genotypes on the Pharmacokinetics of Carbamazepine when used as Monotherapy or Co-Administered with Phenytoin, Phenobarbital or Valproic Acid in Thai Patients

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3q888 ◽

2013 ◽

Vol 16 (4) ◽

pp. 502 ◽

Cited By ~ 11

Author(s):

Duangchit Panomvana ◽

Tharathorn Traiyawong ◽

Somchai Towanabut

Keyword(s):

Valproic Acid ◽

Real Time ◽

Statistical Significance ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Allelic Discrimination Assay ◽

Allelic Discrimination ◽

Single Nucleotide ◽

Drug Concentrations ◽

Polymerase Chain

Purpose: To determine the effects of CYP3A5 polymorphisms on carbamazepine (CBZ) pharmacokinetic parameters when CBZ is used either as monotherapy or co-administered with phenytoin (PHT), phenobarbital (PB) or valproic acid (VPA). Methods: Retrospective data were collected from an electronic database and medical records. Blood samples were obtained and drug concentrations analyzed as a part of routine therapeutic drug monitoring (TDM). Screening for wild-type CYP3A5*1 and CYP3A5*3 single nucleotide polymorphism (rs776746) by allelic discrimination assay using real-time polymerase chain reaction technique (real-time PCR) was performed. Pharmacokinetic parameters of CBZ; clearance and dose-adjusted CBZ levels in patients with different genotypes were calculated and compared. Results: Of the 70 patients assessed, 8 (11%) patients were homozygous CYP3A5*1/*1, 28 (40%) patients were heterozygous CYP3A5*1/*3, and 34 (49%) patients were homozygous CYP3A5*3/*3. The CBZ clearance and dose-adjusted CBZ levels did not significantly differ between patients with CYP3A5*1 and CYP3A5*3 alleles when CBZ was used as monotherapy. For patients who used CBZ in combination with an enzyme-inducing antiepileptic drug (AED: PHT or PB), individuals carrying the CYP3A5*1 allele (CYP3A5 expressers) showed a trend of having higher CBZ clearance and lower dose-adjusted CBZ level as compared to individuals carrying the CYP3A5*3 allele, even though no statistical significance was recorded. Nevertheless, it was observed that AEDs significantly increased CBZ clearance only in patients carrying the active CYP3A5*1 allele. Conclusions: When CBZ was used in combination with enzyme-inducing AED, CYP3A5 expressers yielded a trend toward greater susceptibility to change in CBZ clearance and showed lower dose-adjusted CBZ levels compared to CYP3A5 non-expressers. The dosage regimen should be adjusted accordingly to gain a better clinical outcome.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Pharmacokinetics and Renal Disposition of Polymyxin B in an Animal Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01333-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5724-5727 ◽

Cited By ~ 46

Author(s):

Kamilia Abdelraouf ◽

Jie He ◽

Kimberly R. Ledesma ◽

Ming Hu ◽

Vincent H. Tam

Keyword(s):

Renal Insufficiency ◽

Kidney Tissue ◽

Polymyxin B ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Serum Samples ◽

Time Curve ◽

Renal Disposition ◽

Drug Concentrations ◽

Serial Serum

ABSTRACTThe increasing prevalence of multidrug-resistant Gram-negative infections has led to the resurgence of systemic polymyxin B, but little is known about its pharmacokinetics. The objective of this study was to characterize the pharmacokinetics and renal disposition of polymyxin B. Eight female Sprague-Dawley rats (weight, 225 to 250 g) were administered a single intravenous polymyxin B dose (4 mg/kg of body weight). Serial serum samples were collected and assayed for major polymyxin B components using a validated ultraperformance liquid chromatography-tandem mass spectrometry method. The best-fit pharmacokinetic parameters of each component were derived and compared using one-way analysis of variance. Cumulative urine was also collected daily for 48 h and assayed for polymyxin B. Kidney drug concentrations were measured at 6 h (n= 3) and 48 h (n= 3) after the same dose. Additionally, three rats were administered 2 doses of intravenous polymyxin B (4 mg/kg) 7 days apart. Serial serum samples were collected pre- and post-renal insufficiency (induced by uranyl nitrate) and assayed for polymyxin B. The pharmacokinetic parameters of the major components did not appear to be significantly different (P> 0.05). Less than 1% of the dose was recovered unchanged in urine collected over 48 h following administration. Therapeutic drug concentrations persisted in kidney tissue at 48 h. The post-renal insufficiency to pre-renal insufficiency ratio of the area under the serum concentration-time curve from time zero to infinity was 1.33 ± 0.04. Polymyxin B components appear to have similar pharmacokinetics. Polymyxin B preferentially persists in kidneys, which suggests a selective uptake process in renal cells. A mechanism(s) other than renal excretion could be involved in polymyxin B elimination, and dosing adjustment in renal insufficiency may not be necessary.

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Rifampin pharmacokinetics in tuberculosis-diabetes mellitus patients: a pilot study from Baja California, Mexico

The International Journal of Tuberculosis and Lung Disease ◽

10.5588/ijtld.18.0739 ◽

2019 ◽

Vol 23 (9) ◽

pp. 1012-1016

Author(s):

R. Perea-Jacobo ◽

R. Muñiz-Salazar ◽

R. Laniado-Laborín, ◽

A. Cabello-Pasini, ◽

R. Zenteno-Cuevas, ◽

...

Keyword(s):

Diabetes Mellitus ◽

High Performance ◽

Baja California ◽

Serum Levels ◽

High Performance Liquid Chromatographic ◽

Tb Treatment ◽

Routine Monitoring ◽

Liquid Chromatographic ◽

Higher Doses

BACKGROUND: Worldwide, there has been an increase in type 2 diabetes mellitus (DM2) as a comorbidity of tuberculosis (TB), which is characterized by alterations in the pharmacokinetics of drugs used for TB treatment.OBJECTIVE: To characterize the pharmacokinetics of rifampin in patients with TB and TB-DM2.METHODS: Blood samples were collected in two hospitals in Baja California, Mexico from March through December 2017. Sampling was not random and included 14 patients with TB and 16 with TB-DM2. High-performance liquid chromatographic (HPLC) was carried out to determine the concentration of rifampin in human serum.RESULTS: On average, the highest concentration of rifampin for both groups was registered at 2.5 h after ingestion (3.5 ± 2.64 μg/ml). The maximum difference in concentration (Cmax) of rifampin between TB and TB-DM2 group was not significant (P > 0.05). Importantly however, the analysis showed suboptimal levels of Cmax in a high proportion of both groups of patients studied.CONCLUSION: The study suggests that under the currently recommended rifampin dose, suboptimal Cmax levels are reached in a high proportion of patients, regardless of whether they have diabetes or not. It may therefore be necessary to use higher doses of rifampin and perform routine monitoring of serum levels. However, further work is needed to confirm these findings.

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Predictive Techniques Applied to Imipramine Therapeutic Drug Monitoring

DICP ◽

10.1177/106002808902300508 ◽

1989 ◽

Vol 23 (5) ◽

pp. 389-394

Author(s):

M. Mar Fernandez de Gatta ◽

Milagros Tamayo ◽

Maria José Garcia ◽

Cristobal Montojo ◽

J. Ramón Gutierrez ◽

...

Keyword(s):

Steady State ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Prediction Error ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Serum Concentrations ◽

Drug Concentrations ◽

Steady State Serum

The aim of this study was to establish the performance of pharmacokinetic methods employing little data on serum drug concentrations obtained in routine therapeutic drug monitoring of imipramine. Forty-three and 123 serum levels were obtained in 8 adult depressive patients (aged 57–80 y) and 34 enuretic children (aged 5–13 y), respectively. Forecasting of the serum concentrations was performed based on mean population pharmacokinetic parameters (method A), with knowledge of one steady-state serum concentration (method B), and from two or more steady-state serum concentrations (method C). The accuracy and precision of each method were evaluated from the mean prediction error (ME) and from the root mean squared prediction error (RMSE), respectively. The values of ME and RMSE of methods B and C proved to be significantly lower than those found using method A. Method C was the most precise and accurate in both populations. Method A underestimates the serum concentrations observed in adults (ME >0) but overestimates them in children (ME <0), although to a lesser extent. The study shows that it is possible to obtain a good estimation of individual dosage needs from one or more serum concentrations obtained at steady state. Clinical application of these methods (B and C) yields an increase in the efficiency and safety of the treatment, particularly in special populations such as geriatric and pediatric patients.

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Type 2 Diabetes Mellitus Related Distress in Thailand

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17072329 ◽

2020 ◽

Vol 17 (7) ◽

pp. 2329 ◽

Cited By ~ 2

Author(s):

Kongprai Tunsuchart ◽

Peerasak Lerttrakarnnon ◽

Kriengkrai Srithanaviboonchai ◽

Surinporn Likhitsathian ◽

Sombat Skulphan

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Health Care ◽

Type 2 Diabetes Mellitus ◽

Family Support ◽

Linear Regression Analysis ◽

Multiple Linear Regression Analysis ◽

Primary Health ◽

Co Morbidity

This study aimed to investigate prevalence and factors potentially associated with diabetes-related distress (DRD) among type 2 diabetes mellitus (T2DM) patients in a primary health care center in Thailand. This cross-sectional study was conducted with a total of 370 patients with T2DM. Data were collected at primary health care centers in Hang Dong District, Chiang Mai Province, Thailand. DRD was assessed using the Diabetes Distress Scale (DDS-17). The association between sociodemographic characteristics and other factors with DRD was analyzed using the Fisher t-test, Chi-square test, and Pearson’s correlation coefficient test. The association between Hemoglobin A1c (HbA1c) and DRD was analyzed using multiple linear regression analysis. The participants had a mean age of 60.95 ± 7.96, and most were female (68.1%). Of the participants with DRD, 8.9% had moderate to high levels of distress. Education level and family support were significantly associated with the overall level of DRD. Additionally, HbA1c and co-morbidity were also significantly associated with DRD, as were emotional burden and regimen distress. Multiple linear regression analysis found that increased HbA1c was positively associated with increased DRD after adjusting for age, sex, education, duration of T2DM, co-morbidity, diabetic complications, and family support. Screening with DRD may be beneficial in T2DM patients.

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Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01701-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 12

Author(s):

Sampson Antwi ◽

Hongmei Yang ◽

Anthony Enimil ◽

Anima M. Sarfo ◽

Fizza S. Gillani ◽

...

Keyword(s):

Drug Dose ◽

Pharmacokinetic Parameters ◽

Oral Clearance ◽

First Line ◽

Time Curve ◽

Apparent Oral Clearance ◽

Tb Treatment ◽

Hiv Coinfection ◽

Drug Concentrations ◽

Immunodeficiency Virus

ABSTRACT Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC0–8), maximum concentration (C max), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P < 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC0–8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC0–8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

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Effects of the combination of second-generation antipsychotics on serum concentrations of aripiprazole and dehydroaripiprazole in Chinese patients with schizophrenia

General Psychiatry ◽

10.1136/gpsych-2020-100423 ◽

2021 ◽

Vol 34 (2) ◽

pp. e100423

Author(s):

Ping Jiang ◽

Xiujia Sun ◽

Juanjuan Ren ◽

Hongmei Liu ◽

Zhiguang Lin ◽

...

Keyword(s):

Clinical Significance ◽

High Performance ◽

Second Generation ◽

Statistical Significance ◽

Linear Regression Analysis ◽

Multiple Linear Regression Analysis ◽

Chinese Patients ◽

Therapeutic Drug ◽

Serum Concentrations ◽

Second Generation Antipsychotics

BackgroundAripiprazole (ARI) is often prescribed alone or in combination with other second-generation antipsychotics (SGAs) to treat patients with schizophrenia. However, this may increase the potential clinical significance of drug–drug interactions. Therapeutic drug monitoring (TDM) is an important and fundamental tool both when administering ARI alone and in combination with other SGAs to monitor ARI pharmacokinetics, adjust the dosage and thereby achieve more effective and safer treatment.AimsThis study retrospectively investigated the effects of four SGA comedications (clozapine, risperidone, quetiapine (QTP) and olanzapine) and other potential factors (sex, age and ARI dose) on the serum concentrations of ARI and dehydroaripiprazole (DARI) in Chinese patients with schizophrenia using TDM data.MethodsHigh-performance liquid chromatography was used to test the serum concentrations of ARI, DARI and ARI+DARI. In addition, steady-state dose-adjusted serum concentrations (ie, concentration-to-dose ratios, C:D ratios) of ARI, DARI and ARI+DARI; sex; age; ARI dose and SGA comedication dose between 299 inpatients with schizophrenia who received ARI or SGA comedication were all collected and analysed. Spearman’s correlation and multiple linear regression analysis were used to evaluate bivariate associations between ARI dose and serum ARI and DARI concentrations and describe the effect of independent variables on serum ARI and DARI concentrations, respectively.ResultsThere were significant differences in the C:D ratios of ARI (χ2=−3.21, p=0.001) and ARI+DARI (χ2=−2.50, p=0.01) between the ARI and SGA groups, as well as in the C:D ratios of ARI (χ2=−3.59, p<0.001) and ARI+DARI (χ2=−3.10, p=0.002) between the female patients in the two groups. Of the four SGAs, only QTP had significant effects on the C:D ratios of ARI (Z=−4.12, p<0.001) and ARI+DARI (Z=−3.62, p<0.001) when compared with the ARI group in the whole sample and on the C:D ratios of ARI, DARI and ARI+DARI (Z=−3.96, p<0.001; Z=−2.22, p=0.03; Z=−3.75, p<0.001, respectively) in women when compared with their counterparts in the ARI group.ConclusionComedication with SGAs resulted in lower C:D ratios of ARI and ARI+DARI compared with ARI monotherapy, and comedication with QTP resulted in lower C:D ratios of ARI and ARI+DARI than ARI monotherapy. Despite this statistical significance of our findings, whether the presently observed effect has clinical significance requires exploration by further research. TDM and dosage regulation of ARI should be performed in Chinese inpatients with schizophrenia who are receiving SGA comedication (especially QTP) to maintain a safe and effective dose-adjusted serum concentration of ARI and DARI.

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