HRZE Fasted/Fed in Newly Diagnosed TB (FASTFOOD)

The Influence of Fasting and Food on the Pharmacokinetics of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol in Newly Diagnosed TB Patients

WHO recommends to take TB drugs while fasting: if TB drugs are taken with food, perhaps drug concentrations are too low; on the other hand: if this is not tolerated, drugs could also be taken with food.

Do lower drug concentrations - with improved adherence to therapy - outweigh the disadvantage of lower drug blood concentrations over time? How exactly do the drug concentrations over time (pharmacokinetics) compare between fasting and fed conditions, especially in the early stage of TB treatment when patients are relatively sick, and relatively poorly tolerate TB drugs?

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: intravenous administration of 1st line TB drugs, day 1

Detailed Description

To evaluate the influence of concomitant food ingestion on the pharmacokinetics of HRZE in newly diagnosed TB patients To evaluate the influence of early disease on the PK parameters of HRZE in TB patients To compare the pharmacokinetics of HRZE in the early stage of disease with the pharmacokinetics of HRZE in more stable condition in newly diagnosed TB patients To evaluate adverse events of HRZE in TB patients

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Indonesia
  • Yogyakarta, Indonesia
    • Sardjito Central Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with TB who are starting with HRZE therapy
• Age > 18 years old
• Written informed consent

Exclusion Criteria:

• Use of antacids, which cannot be discontinued for study days
• Active, unstable hepatic disease (with jaundice, HRZ)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fasting-Fed; blood sampling on 3 consecutive days; by randomization, drug treatment as follows: day 1, HRZE as iv therapy; on day 2, HRZE as oral therapy in fasting condition (2 hours before meals); and on day 3 HRZE as oral therapy in fed condition (after meals).	Drug: intravenous administration of 1st line TB drugs, day 1; TB drugs IV on day 1 for calculation of bioavailability while fasting or fed
Active Comparator: Fed-Fasting; blood sampling on 3 consecutive days; by randomization, drug treatment as follows: day 1, HRZE therapy as iv therapy; day 2, HRZE as oral therapy in fed condition, and on day 3, HRZE as oral therapy in fasting condition	Drug: intravenous administration of 1st line TB drugs, day 1; TB drugs IV on day 1 for calculation of bioavailability while fasting or fed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pharmacokinetics	pharmacokinetics (AUC0-8, Cmax, and Tmax); comparison between TB patients who take HRZE concomitant with food and TB patients who take HRZE concomitant without food, weeks 1 and 8 of treatment	3 days - week 1 and week 8
pharmacokinetics (AUC0-8, Cmax, and Tmax) of HRZE	PK curves from venous blood specimens sampled from indwelling venous catheter	11 time points, 3 consecutive days - wk 1 & 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate adverse events of HRZE, week 1 and 8 - while taking food or not	tolerance - acceptance; vomiting, refusal	week 1 - week 8

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
confounding factors for primary and secondary outcomes	Parameters which may influence the pharmacokinetics of HRZE will be measured at start and end of the study.; BMI, i.e. body weight and length; age; gender; ethnicity; co-morbidity, for instance HIV/AIDS, diabetes (only at start); co-medication: especially HIV medication, prednisolone (may lower INH concentration), antacids (may lower absorption of HRE concentration); chemistry: liver function, renal function, hemoglobulin, albumin, bilirubin; pharmacogenetics	weeks 1 and 8

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: University of Groningen; Gadjah Mada University

Publications and helpful links

General Publications

• Saktiawati AMI, Harkema M, Setyawan A, Subronto YW, Sumardi, Stienstra Y, Aarnoutse RE, Magis-Escurra C, Kosterink JGW, van der Werf TS, Alffenaar JC, Sturkenboom MGG. Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis. Clin Pharmacokinet. 2019 Nov;58(11):1445-1454. doi: 10.1007/s40262-019-00763-3.
• Saktiawati AM, Sturkenboom MG, Stienstra Y, Subronto YW, Sumardi, Kosterink JG, van der Werf TS, Alffenaar JW. Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: a randomized cross-over trial. J Antimicrob Chemother. 2016 Mar;71(3):703-10. doi: 10.1093/jac/dkv394. Epub 2015 Dec 11.

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: January 25, 2014
• First Submitted That Met QC Criteria: April 22, 2014
• First Posted (Estimate): April 23, 2014

Study Record Updates

• Last Update Posted (Estimate): April 8, 2015
• Last Update Submitted That Met QC Criteria: April 7, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: bioavailability; TB; fasting; fed; HRZE
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: UGM-RuG-UMCG-TB-001