Variability in plasma rifampicin concentrations and role of SLCO1B1, ABCB1, AADAC2 and CES2 genotypes in Ethiopian patients with tuberculosis

Figures & data

Table 1. Sociodemographic and clinical characteristics of 119 Ethiopian tuberculosis patients.

Variables		Pulmonary TB (n = 78)	Extrapulmonary TB (n = 41)	All patients (n = 119)
Sex (n)	Male	45	17	62 (52.5%)
	Female	33	24	57 (47.5%)
Smoking (n)	Yes	15	1	16 (13.4%)
	No	63	40	103 (86.6%)
Khat chewer (n)	Yes	20	2	22 (18.5%)
	No	58	39	97 (81.5%)
Alcohol (n)	Yes	17	3	20 (16.8%)
	No	61	38	99 (83.2%)
Age (years), median (IQR)		26 (21–35)	28 (24.5–36)	28 (22–35)
Median body weight in kg (IQR)		53 (45–60)	58 (52.5–68.5)	54.75 (48–61.75)
Drug dose (mg/kg, SD)		9.46 (0.99)	9.26 (0.98)	9.39 (0.98)
Median Cmax, µg/mL (IQR)		6.45 (5.13–8.54)	7.46 (6.02–8.72)	6.75 (5.39–8.58)
Median AUC0–7 µg.h/mL (IQR)		16.52 (13.81–21.98)	17.55 (14.3–22.59)	17.05 (13.87–22.26)

AUC_0–7 h: area under the time-concentration curve; C_max: maximum concentration; n: number; IQR: interquartile range; SD: standard deviation.

Table 2. Genotype and variant allele frequency of SLCO1B1, ABCB1, AADAC and CES-2.

Variant allele	Protein	Genotype frequency (n, %)			Allele frequency (%)		χ^2	p value
SLCO1B1*1B (c.388A > G)	Asn130Asp	A/A (15, 12.6)	A/G (60, 50.4)	G/G (37, 44)	A (37.7)	G (62.2)	0.618	0.43
SLCO1B1*5 (c.521T > C)	Val174Ala	T/T (76, 63.9)	T/C (38, 31.9)	C/C (5, 4.2)	T (79.8)	C (20.2)	0.008	0.99
ABCB1 c.3435C > T	Ile1145Ile	C/C (67, 56.3)	C/T (46, 38.7)	T/T (6, 5.0)	C (75.6)	T (24.4)	0.28	0.59
ABCB1c.4036A > G	Located in 3′-UTR	A/A (88, 73.8)	A/G (28, 23.5)	G/G (3, 2.5)	A (85.4)	G (14.6)	0.183	0.67
AADAC*2 (c.841G > A)	Val281Ile	G/G (3, 2.5)	G/A (26, 21.7)	A/A (90, 75)	G (13.9)	A (86.1)	0.447	0.5
CES-2 c.269-965A > G	Located in intron 1	A/A (55, 46.2)	A/G (55, 46.2)	G/G (9, 7.6)	A (69.4)	G (30.6)	0.896	0.34

n: number; UTR: untranslated region. The chi-square test and p value show correlations between the observed and expected genotype frequencies according to the Hardy–Weinberg equilibrium.

Table 3. Effects of SLCO1B1, ABCB1, AADAC and CES-2 genotype on rifampicin C_max and AUC_0–7 h in Ethiopian TB patients (n = 119).

Genotype		N	Cmax (µg/mL)			AUC0–7 (µg h/mL)
			Median (IQR)	Geometric mean ± SE	p Value*	Median (IQR)	Geometric mean ± SE	p value*
SLCO1B1*1B (c.388A > G)	A/A	15	6.88 (5.83–9.36)	7.08 ± 1.1	0.87	17.95 (16.59–20.93)	17.78 ± 1.12	0.67
	A/G	60	6.62 (6.23–7.75)	6.76 ± 1.05		16.35 (14.36–18.22)	16.6 ± 1.05
	G/G	44	6.82 (6.1–7.4)	6.92 ± 1.05		17.14 (15.35–18.78)	17.78 ± 1.07
SLCO1B1*5 (c.521T > C)	T/T	76	6.59 (6.18–7.02)	6.76 ± .05	0.15	16.65 (15.08–18.12)	16.98 ± 1.05	0.18
	T/C	38	7.62 (6.76–8.12)	7.24 ± 1.07		18.49 (17.03–22.4)	18.2 ± 1.07
	C/C	5	5.1 (4.76–7.41)	5.37 ± 1.1		12.5 (12.44–19.61)	13.18 ± 1.12
ABCB1 c.3435C > T	C/C	67	6.42 (6.1–7.2)	6.61 ± 1.05	0.70	16.7 (15.08–18.22)	16.98 ± 1.05	0.87
	C/T	46	7.23 (6.63–7.95)	6.92 ± 1.07		17.85 (16.48–19.73)	17.78 ± 1.07
	T/T	6	6.76 (6.1–10.43)	7.24 ± 1.15		14.68 (13.4–23.99)	16.6 ± 1.12
ABCB1 c.4036A > G	A/A	88	6.53 (6.10–7.18)	6.61 ± 1.05	0.018	16.7 (15.08–17.77)	16.6 ± 1.05	0.02
	A/G	28	7.29 (6.59–8.85)	7.41 ± 1.07		18.31 (15.5–23.09)	18.2 ± 1.07
	G/G	3	9.35 (7.07–18.57)	10.72 ± 1.32		32.13 (17.3–47.05)	29.51 ± 1.35
AADAC2 c.841G > A	A/A	90	7.045 (6.49–7.82)	7.08 ± 1.05	0.047	17.56 (16.48–18.58)	17.78 ± 1.05	0.16
	G/A	26	6.21 (4.85–6.79)	6.03 ± 1.07		15.06 (14.11–20.29)	15.49 ± 1.07
	G/G	3	4.69 (4.27–6.63)	5.13 ± 1.15		13.99 (9.92–16.59)	13.18 ± 1.17
CES-2 c.269-965A > G	A/A	55	7.18 (6.59–8.04)	7.08 ± 1.05	0.08	17.85 (15.5–19.06)	17.38 ± 1.05	0.19
	A/G	55	6.42 (6.10–7.2)	6.31 ± 1.05		16.58 (14.82–17.3)	16.22 ± 1.05
	G/G	9	6.87 (6.18–13.94)	8.13 ± 1.15		18.32 (15.08–29.74)	21.38 ± 1.15

AUC_0–7 h: area under the time-concentration curve; C_max: maximum concentration; n: number; IQR: interquartile range; SE: standard error; GM: geometric mean; TB: tuberculosis. *p value from analysis of variances using log₁₀ transformed C_max and AUC_0–7 h data.

Figure 1. Comparison of rifampicin C_max and AUC_0–7 h in the ABCB1 c.4036A > G (right) and AADAC2 c.841G > A (left) genotypes. The box plots show the median ± interquartile range, whereas whiskers denote the minimum and maximum values.

Table 4. Univariate and multivariate linear regression analysis of factors associated with rifampicin log₁₀C_max and log₁₀AUC_0–7 h in Ethiopian adult tuberculosis patients.

Variable	Cmax				AUC
	Univariate		Multivariate		Univariate		Multivariate
	Beta coefficients (95% CI)	p value	Adjusted beta coefficients (95% CI)	p value	Beta coefficients (95% CI)	p value	Adjusted beta coefficients (95% CI)	p value
Age	0.002 (−0.001 to 0.006)	0.12	0.002 (−0.048 to 0.004)	0.24	0.002 (−0.001 to 0.006)	0.19	0.002 (−0.002 to 0.005)	0.31
Sex (female vs. male)	−0.051 (−0.11 to 0.003)	0.06	−0.056 (−0.11 to 0.004)	0.03	−0.057 (−0.12 to 0.04)	0.07	−0.063 (−0.12 to 0.03)	0.04
Drug dose (mg)	0.00 (0.00 to 0.001)	0.05	0.000 (0.00 to 0.001)	0.03	0.000 (0.00 to 0.01)	0.05	0.000 (0.00 to 0.01)	0.03
Alcohol use (no vs. yes)	0.00 (−0.066 to 0.8)	0.84			0.002 (−0.08 to 0.083)	0.97
Khat chewing (no vs. yes)	0.00 (−0.074 to 0.067)	0.91			0.013 (−0.066 to 0.093)	0.74
Smoking (no vs. yes)	−0.012 (−0.093 to 0.067)	0.75			0.016 (−0.076 to 0.11)	0.73
Days on drug therapy	−0.001 (−0.004 to 0.0012)	0.43			0.001 (−0.005 to 0.003)	0.59
SLCO1B1c.388A > G	−001 (−0.043 to 0.04)	0.96			0.007 (−0.04 to 0.054)	0.76
SLCO1B1c.521T > C	0.002 (−0.05 to 0.046)	0.94			0.002 (−0.052 to 0.056)	0.95
ABCB1 c.3435C > T	0.02 (−0.026 to 0.066)	0.4			0.006 (−0.046 to 0.059)	0.81
ABCB1 c.4036A > G	0.071 (0.018 to 0.124)	0.009	0.063 (0.013 to 0.114)	0.015	0.071 (0.011 to 0.13)	0.02	0.059 (0.001 to 0.13)	0.048
AADAC*2c.841G > A	−0.068 (−0.122 to −0.014)	0.01	−0.065 (−0.12 to −0.013)	0.015	−0.059 (−0.12 to 0.001)	0.06	−0.059 (−0.12 to 0.001)	0.053
CES-2 c.269-965A > G	−0.004 (−0.048 to0.04)	0.86			0.008 (−0.043 to0.058)	0.76

AUC_0–7 h: area under the time-concentration curve; C_max: maximum concentration; CI: confidence interval.