The Impact of First-Line Anti-Tubercular Drugs’ Pharmacokinetics on Treatment Outcome: A Systematic Review

Figures & data

Table 1 Basic Pharmacokinetics of First-Line Anti-Tubercular Drugs¹⁶

Drug Name	Dose	Serum Cmax (µg/mL)	Tmax (hr)	Serum T½ (hr)
Rifampicin	600mg	8–24	2	2–3
Isoniazid	300mg	3–6	0.75–2	1.5 fast 4 slow
Pyrazinamide	25–35mg/kg	20–60	1–2	9
Ethambutol	25mg/kg	2–6	2–3	Biphasic: 2–4, then 12–14

Figure 1 PRISMA flow diagram showing the literature search for studies which described drug pharmacokinetics of first line tuberculosis drugs and treatment outcomes.

Abbreviations: PK, pharmacokinetics; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiology. 2009;62(10). Creative Commons.

Table 2 Characteristics of Included Studies

Author	Country	Mean (Median) Age of Study Participant	Study Design	Sample Size	Population Characteristics	Risk of Bias
Aarnoutse, (2017)^Citation30	Tanzania	33.5	Randomized Controlled Trial	150	15 HIV positive	Low
Burhan (2013)^Citation34	Indonesia	35	Prospective cohort	181	44 diabetic 19 HIV positive	Low
Pasipanodya (2013)^Citation25	South Africa	36	Prospective cohort	142	15 HIV positive 98 have prior tuberculosis	Low
Prahl (2014)^Citation31	Denmark	42	Prospective cohort	32	2 HIV positive	Low
Requena-Méndez (2014)^Citation33	Peru	29	Prospective cohort	107	25 Diabetic 30 HIV positive	Low
Rockwood (2017)^Citation29	South Africa	33	Prospective cohort	100	65 HIV positive 4 diabetic	Low
Sekaggya-Wiltshire (2018)	Uganda	34	Prospective cohort	227	All HIV positive	Low
Svensson (2018)^Citation27	Tanzania and South Africa	34	Prospective cohort	97	2 patients HIV positive	Low
Vela´ squez (2018)^Citation32	Peru	25	Randomized Controlled Trial	180 randomized to three arms 10, 15, and 20 mg/kg	2 patients HIV positive	Low
Gengiah (2014)^Citation26	South Africa	33	Prospective cohort	57	All are HIV positive	Low
Ramachandran (2017)^Citation35	India	38	Prospective cohort	1912	19 HIV positive 53 diabetic	Low
Ramachandran (2020)^Citation36	India	39.5	Prospective cohort	404	27 HIV infected 113 Diabetics	Low

Table 3 Pharmacokinetic Characteristics and Treatment Outcome

Author	Study Drug	Pharmacokinetics Bio-Analytical Methods	PK Parameter Considered	PK Sampling Time	Duration for Which the Study Participant Followed	Outcome Measured	The Proportion of Patient with Low PK	The Proportion of Patients with Poor Outcome	Conclusion on the Predictive of PK on Treatment Outcome at the End of Treatment
Aarnoutse, (2017)^Citation30	RMP	ultraperformance liquid chromatographic	Cmax	1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 24 hours	12 weeks	Time to culture conversion on different days	NA	72.2% from 600mg 62.9 from 900mg 73.8% from 1200mg have culture conversion on 84 days	Higher exposure to RMP was observed as the dose increase., but did not result in an improved bacteriological response in patients with pulmonary TB
Burhan (2013)^Citation34	INH, RMP, PZA	HPLC	Cmax	2 hours	8 weeks	Culture conversion at 8 weeks	INH= 88% RMP= 49% PZA=2%	11/155 have a positive culture at week 8	No association was found between drug concentration and 8 weeks of culture conversion
Pasipanodya (2013)^Citation25	INH, RMP, PZA	HPLC with UV detection for RMP, INH, and PZA; mass spectrometry for EMB	24-hours AUC l	0.5, 1, 1.5, 2, 2.5, 3, 4, 6, and 8 hours	For up to 2 years	Culture conversion at two months and long term outcome up to two years	PZA=69.7% RMP =70.7% INH =81%	11/142 did not convert culture at two months 25% of 142 patients had poor long-term outcomes	From CART analysis Low drug AUCs are predictive of clinical outcomes in tuberculosis patients PZA: AUC < 363 RMP: AUC <13 INH: AUC < 52
Prahl (2014)^Citation31	INH, RMP, EMB, PZA	HPLC with tandem mass spectrometry	2 hours of concentration	2hours	For up to one year after completion of treatment	Failure at six months or a relapse of TB within 1 year after the end of treatment	INH= 71%, RMP=57.6% EMB= 46% PZA=10%	5/28 failure during one year follow up	Lower INH and RMP are observed in treatment failure
Requena-Méndez (2014)^Citation33	INH	HPLC with a triple-quadrupole TSQ Quantum Access mass spectrometer	Cmax, and AUC(0–6h)	2 and 6 hours	6 months after completion of treatment	outcomes at the end of therapy and 6 months after the end of therapy	34% during the intensive phase and 33.3% during the continuation phase	4/41 (2 death, 1 relapse, and 1 prolonged treatment)	Unable to demonstrate a clear relationship between the Cmax of INH and treatment outcome
Rockwood (2017)^Citation29	INH, RMP, PZA	HPLC with Tandem mass spectrometry	Cmax AUC24 AUC0-24/MIC, Cmax/MIC	1, 2, 3, 4, 6, and 8 hours	2 months culture conversion	Culture conversion at two months	INH 43% Cmax <3 mg/L) and 6% <1.5 mg/L. RMP 80% Cmax <8 mg/L and 17% <4 mg/L. PZA 53% Cmax <35 mg/L and 1% <20 mg/L	13% overall treatment success without failure/relapse was observed	None of these Cmax cutoff values for INH or RMP predicted 2-month culture conversion and/or failure/relapse but did predict failure/relapse for PZA
Sekaggya-Wiltshire (2018)^Citation28	INH, RMP, PZA EMB	HPLC	Cmax and AUC	1, 2, and 4 hours	Up to 24 weeks after initiation of TB treatment	Cure, death, failure	INH =83.7% RMP = 77.5% PZA =2.64%a EMB=30.8%	Cure=158 Death = 11 Failure =8 Default = 2 Lost to follow up = 17	Patients with both low RMP and INH Cmax have moderately increased risk of unfavorable treatment outcomes, including death, failure, loss to follow-up, and default
Svensson, (2018)^Citation27	RMP	ultraperformance HPLC	AUC24	0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours	Up to 26 weeks	time to stable sputum culture conversion (TSCC)	NA	NA	Increasing RMPampicin exposure to modestly shorter TSCC at week 8, TSCC increased from 39% to 55% with RMP AUC0–24h increasing from 20 to 175 mg/L·h
Vela´ squez (2018)^Citation32	RMP	NA	AUC24/MIC	NA	Up to 12 months	Change in elimination rate of M. tuberculosis log10 colony-forming units- and culture conversion at 8 week and unfavorable outcome at 12 months	NA	At 12 month cure 10mg/kg =44/60, 15 mg/kg= 46/60 And 20mg/kg =46/60	Increasing the dose enhanced rapid sputum sterilization
Gengiah (2014)^Citation26	RMP	Tandem HPLC mass spectrometry	Cmax	2.5 hours	Up to 6 months	Sputum at six months	All	8/55 sputum positive at two months 2/51 sputum positive at six months	No evidence, but in all patients Cmax is below the standard target
Ramachandran (2017)^Citation35	RMP INH, and PZA	HPLC	2 hours plasma concentration	2hours	Up to end of therapy	Outcome at the end of treatment	RMP= 91%, INH= 16%, PZA = 17%	264 (14%) had an unfavorable outcome	Low RMP concentration is among the factors associated with treatment outcome
Ramachandran (2020)^Citation36	RMP INH, and PZA	HPLC	2 hours of plasma concentration	2hours	Up to 2 years (24 months)	Outcome during the follow-up period	NA	77 (19%) patients have an unfavorable outcome	Low RMP and PZA concentrations were associated with poor outcomes

Abbreviations: NA, nonapplicable; RMP, rifampicin; INH, isoniazid; PZA, pyrazinamide; EMB, ethambutol; PK, pharmacokinetics; AUC, area under the curve; HPLC, high-performance liquid chromatographic.

Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs. 2014;74(8):839–854. doi:10.1007/s40265-014-0222-824846578

 PubMed Web of Science ®Google Scholar

Aarnoutse RE, et al. Pharmacokinetics, tolerability, and bacteriological response of rifampin administered at 600, 900, and 1200 milligrams daily in patients with pulmonary tuberculosis. Antimicrob Agents Chemother. 2017;61(11).

 Web of Science ®Google Scholar

Burhan E, Ruesen C, Ruslami R, et al. Isoniazid, rifampin, and pyrazinamide plasma concentrations in relation to treatment response in Indonesian pulmonary tuberculosis patients. Antimicrob Agents Chemother. 2013;57(8):3614–3619. doi:10.1128/AAC.02468-1223689725

 PubMed Web of Science ®Google Scholar

Pasipanodya JG, McIlleron H, Burger A, et al. Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis. 2013;208(9):1464–1473. doi:10.1093/infdis/jit35223901086

 PubMed Web of Science ®Google Scholar

Prahl JB, Johansen IS, Cohen AS, et al. Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study. J Antimicrob Chemother. 2014;69(10):2841–2847. doi:10.1093/jac/dku21025140577

 PubMed Web of Science ®Google Scholar

Requena-Mendez A, Davies G, Waterhouse D, et al. Effects of dosage, comorbidities, and food on isoniazid pharmacokinetics in Peruvian tuberculosis patients. Antimicrob Agents Chemother. 2014;58(12):7164–7170. doi:10.1128/AAC.03258-1425224007

 PubMed Web of Science ®Google Scholar

Rockwood N, Pasipanodya JG, Denti P, et al. Concentration-dependent antagonism and culture conversion in pulmonary tuberculosis. Clin Infect Dis. 2017;64(10):1350–1359. doi:10.1093/cid/cix15828205671

 PubMed Web of Science ®Google Scholar

Svensson EM, Svensson RJ, Te Brake LHM, et al. The potential for treatment shortening with higher rifampicin doses: relating drug exposure to treatment response in patients with pulmonary tuberculosis. Clin Infect Dis. 2018;67(1):34–41. doi:10.1093/cid/ciy02629917079

 PubMed Web of Science ®Google Scholar

Velasquez GE, Brooks MB, Coit JM, et al. Efficacy and safety of high-dose rifampin in pulmonary tuberculosis. a randomized controlled trial. Am J Respir Crit Care Med. 2018;198(5):657–666. doi:10.1164/rccm.201712-2524OC29954183

 PubMed Web of Science ®Google Scholar

Gengiah TN, Botha JH, Soowamber D, et al. Low rifampicin concentrations in tuberculosis patients with HIV infection. J Infect Dev Ctries. 2014;8(8):987–993. doi:10.3855/jidc.469625116663

 PubMed Web of Science ®Google Scholar

Ramachandran G, et al. Factors influencing tuberculosis treatment outcome in adult patients treated with thrice-weekly regimens in India. Antimicrob Agents Chemother. 2017;61(5).

 Web of Science ®Google Scholar

Geetha Ramachandran PC, Gaikwad S, Kupparam HKA, et al. Subtherapeutic rifampicin concentration is associated with unfavorable tuberculosis treatment outcomes. Clin Infect Dis. 2020;70(7):1463–1470. doi:10.1093/cid/ciz38031075166

 PubMed Web of Science ®Google Scholar

Sekaggya-Wiltshire C, von Braun A, Lamorde M, et al. Delayed sputum culture conversion in tuberculosis-human immunodeficiency virus-coinfected patients with low isoniazid and rifampicin concentrations. Clin Infect Dis. 2018;67(5):708–716. doi:10.1093/cid/ciy17929514175

 PubMed Web of Science ®Google Scholar