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)30 | 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)34 | 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)25 |
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)31 | 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)33 | 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)29 | 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)28 |
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)27 | 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)32 | 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)26 | 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)35 | 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)36 | 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.