Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis

Figures & data

Figure 1. Pharmacokinetic/pharmacodynamic integration.

In pharmacokinetic/pharmacodynamic (PK/PD) modeling, both pharmacokinetic (PK) models and pharmacodynamic (PD) models are brought together to provide information about the time at which the concentration of an anti-tuberculosis (anti-TB) drug is within the therapeutic range A. PK model with on the x-axis the time in hours after dosage and on the y-axis the concentration of the anti-TB drug. The dark grey area is the area under the curve (AUC). The maximum of the curve is the peak concentration (C_max), at a certain time (t_max). B. PD model with on the x-axis the plasma concentration of the anti-TB drug and on the y-axis the response in percentage of the maximum effect (E_max). The EC₅₀ is the half maximal effective concentration, which is used as a measure of the anti-TB drug’s potency. C. This graph shows another PD model, but in this case the plasma concentration of the drug at which toxicity occurs is shown. The TD50 is the median toxic dose at which in 50% of the cases toxicity occurs. D. By combining Figure 1B and 1C, the plasma concentration of the anti-TB drug at which the maximum effect is reached with the lowest change of toxicity. This is known as the therapeutic range and is marked with the light grey area.[5]

Table 1. Pharmacokinetic and pharmacodynamic markers of antituberculosis drugs for the use of therapeutic drug monitoring [7,10,18–20].

WHO group [21]	Drug	Adult daily dose* [7,18,20]	Cmax [7,18,20]	Tmax (h) [7,18,20]	PK/PD^b [7,18,20]	PK/PD target value [19,22]	LSS^c	DBS^c
1	Isoniazid	300 mg	3–6 µg/ml	0.75–2	AUC/MIC	19.2 (slow) and 11.6 (fast)	No	No
1	Rifampicin	600 mg	8–24 µg/ml	2	AUC/MIC	40	Yes [11,23]	Yes [24]
1	Rifabutin	300 mg	0.45–0.9 µg/ml	3–4	N/A	N/A	No	No
1	Pyrazinamide	25–35 mg/kg	20–60 µg/ml	1–2	AUC/MIC	52	Yes [16]	No
1	Ethambutol	25 mg/kg	2–6 µg/ml	2–3	AUC/MIC or Cmax/MIC	23 or 10	No	No
2	Streptomycin	15 mg/kg	35–45 µg/ml^d	0.5–1.5 IM	AUC/MIC [19]	8–10^e	No	No
2	Capreomycin	15–30 mg/kg	32 µg/ml	N/A	Cmax/MIC	20	No	No
2	Amikacin	15–30 mg/kg	46 µg/ml	End infusion IV	Cmax/MIC	43	No	No
2	Kanamycin	15–30 mg/kg	44 µg/ml	End infusion IV	Cmax/MIC	20	No	No
3	Ofloxacin	800 mg	10.5 µg/ml	1	AUC/MIC	47	No	No
3	Levofloxacin	500–1000 mg	8–13 µg/ml	1–2	AUC/MIC	N/A	Yes [15]	No
3	Moxifloxacin	400 mg a day	3–5 µg/ml	1–2	AUC/MIC	110.5	Yes[25]	Yes[26]
4	p-Aminosalicylic acid	4000 mg twice daily	20–60 µg/ml (granules)	4–8 (granules)	AUC/MIC [19]	154	No	No
4	Ethionamide	250–500 mg	1.35 µg/ml	2	Cmax/MIC or T > MIC [19]	1.6 or 1.5	No	No
4	Prothionamide	750 mg	2.5 µg/ml	3–4	N/A	N/A	No	No
4	Cycloserine	250–500 mg	8–9 µg/ml	2–3	AUC/MIC [19]	N/A	No	No
4	Terizidone	750 mg	20–30 µg/ml	N/A	N/A	N/A	No	No
5	Clofazimine	100 mg	0.5–2.0 µg/ml	2–7	N/A	N/A	No	No
5	Linezolid	300–600 mg	12–26 µg/ml	1.5	AUC/MIC [19]	80–120 and 100%	Yes [27]	Yes [28]
5	Clarithromycin	1000 mg	2–4 µg/ml	2–4	AUC/MIC	N/A	No	Yes [29]
5	Amoxicillin/clavulanate	1750/250 mg	15–25 µg/ml	1–2.5	T > MIC	N/A	No	No
5	High-dose isoniazid	10 mg/kg (if INH MIC < 1 mg/l) or 16–20 mg/kg three times a week (if INH MIC 1–5 mg/l)	9–15 µg/ml	0.75–2	AUC/MIC	N/A	No	No
5	Thiacetazone [19]	150 mg	1–2.5 µg/ml	2–6	T > MIC	N/A	No	No
5	Imipenem	1000–1500 mg	30–40 µg/ml	2	T > MIC	N/A	No	No
6^f	Bedaquilline [30]	400 mg^g	5.5 µg/ml	2–6	AUC/MIC	N/A	No	No
6^f	Rifapentin^h	600 mg	8–30 µg/ml	5	N/A	N/A	No	Yes [31]
6^f	Pretomanid [32]	200 mg	6 µg/ml	2	T > MIC	100%	No	No
6^f	Delamanid [33]	200 mg	228 ng/ml	4	N/A	N/A	No	No

^aThe adult dosage is based on the dosage that is given a day, while dosing multiple times a day is not performed very often anymore because of compliance.

^bThe PK/PD parameters are based on the parameters that describe the in vivo efficacy of the drug (microbial kill) best.

^cLimited sampling strategies and dried blood spots provide information about the anti-TB drugs that have validated methods for these strategies, marked with yes or no.

^dCalculated C_max using linear regression to 1 h post-IM dose or end of IV infusion.

^eEffective bactericidal activity. >12 is thought to result in maximum killing.

^fOther anti-TB drugs, not included in the WHO list of drugs.

^gFirst 2 weeks, thereafter 200 mg.

^hFor treatment of latent TB infection (LTBI) only.

C_max: Peak concentration; t_max: time at which the peak concentration occurs; PK/PD: pharmacodynamics/pharmacokinetics (integration); LSS: limited sampling strategy; DBS: dried blood spots; AUC: area under the time concentration curve; MIC: minimal inhibitory concentration; N/A: not applicable, no information is available.

Table 2. Drug susceptibility test methods and critical concentrations for first- and second-line drug susceptibility tests together with molecular tests.

					Phenotypic DST
Drug		Genotypic DST			DST critical concentrations (µg/ml) [54]
Group	Drug	Molecular test	Gene	Genes screened with WGS [72]	Löwenstein–Jensen	Middlebook 7H10	Middlebrook 7H11	MGIT960
1	Pyrazinamide		pncA [75] panD [76]	pncA, rpsA	–	–	–	100
	Ethambutol	MTBDRsl v1^a	embB [74]	embA, embB, embC, iniA, iniC, manB,rm1D	2	5	7.5	5
	Rifabutin	MTBDRplus^c	rpoB [77]					0.5
	Isoniazid	MTBDRplus^c	inhA [74] katG [74]	ahpC, fabG1, inhA, katG, ndh	0.2	0.2	0.2	0.1
	Rifampicin	MTBDRplus^c, Xpert/RIF^d [38,54]	rpoB [74]	rpoB	40	1	1	1
2	Kanamycin	MTBDRsl v1^a, v2^b	rrs [74] eis [78]	gidB, rrs, tlyA, eis	30	5	6	2.5
	Amikacin	MTBDRsl v1^a, v2^b	rrs [74]	gidB, rrs, tylA	30	4	–	1
	Capreomycin	MTBDRsl v1^a, v2^b	rrs [74]	gidB, rrs, tylA	40	4	–	2.5
	Streptomycin	MTBDRsl v1^a, v2^b	rrs [79]	rpsL, gidB, rrs, tlyA	4	2	2	1
3	Levofloxacin				–	1	–	1.5
	Moxifloxacin	MTBDRsl v1^a, v2^b	gyrA [74] gyrB[78]	gyrA, gyrB	–	0.5/2	–	0.5/2
	Ofloxacin	MTBDRsl v1^a, v2^b	gyrA [78] gyrB [78]	gyrA, gyrB	4	2	2	2
4	P-aminosalicyclic acid				1	2	8	4
	Cycloserine				30	–	–	–
	Ethionamide	MTBDRplus^c	inhA [80]		40	5	10	5
	Protionamide				40	–	–	2.5
5	Clofazimine				–	–	–	–
	Linezolid				–	–	–	1

DST: Drug susceptibility test; MGIT: mycobacterium growth indicator tube; WGS: whole genome sequencing.

^aGenoType MTBDRsl version 1 (v1) is for the detection of M. tuberculosis complex and its resistance to fluoroquinolones, aminoglycosides/cyclic peptides, and ethambutol.

^bGenoType MTBDRsl version 2 (v2) is for the detection of M. tuberculosis complex and its resistance to fluoroquinolones, aminoglycosides/cyclic peptides.

^cGenoType MTBDRplus is for the detection of M. tuberculosis complex and its resistance to isoniazid and rifampicin.

Xpert/RIF this is a cartridge-based fully automated molecular diagnostic assay for the detection of M. tuberculosis complex and its resistance to rifampicin.

Figure 2. Next generation approach of integrated therapeutic drug monitoring approach including molecular testing and biomarker evaluation.

First, TB is diagnosed, where after drugs are selected based on molecular resistance tests. A baseline biomarker is then selected, which can be followed throughout treatment. The biomarker can help to determine whether the treatment is effective and if changes in the regimen need to be made. TDM is done during the entire course of treatment using the dried blood spot (DBS) approach. TB: tuberculosis; TDM: Therapeutic Drug Monitoring; DBS: Dried Blood Spots.

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