Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review

Figures & data

Figure 1 PRISMA flow diagram showing the literature search for studies that investigated the effect of genetic variations in drug metabolizing enzymes and drug transporters on the pharmacokinetics of rifamycins.

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 1 Summary of the Studies Reported the Drug Transporter (SLCO11 and ABC1B) Gene Polymorphisms Association with Rifamycins Pharmacokinetics Variation

Reference	Gene	SNPs	Characteristics of Study Participant	Rifamycins PK Change Observed
[^Citation31]	SLCO1B1	rs2306283 rs4149032 rs4149056 rs4149015	Tuberculosis recurrent black South African of which 127 (73.8) are HIV positive	No significant association between rifampicin pharmacokinetic and all variants of SLCO1B1 gene SNPs studied was observed
[^Citation43]	SLCO1B1	rs11045819 rs4149032	174 Malawian adults with pulmonary TB of which 98 are HIV-infected patients	No association was reported for both variants of SLCO1B1 gene SNPs studied and the pharmacokinetics of rifampicin
[^Citation32]	SLCO1B1	rs4149032	57 newly diagnosed TB-HIV co-infected South African patients	Lower median concentration of rifampicin at 2.5hr; 3.7 μg/mL in heterozygous and 3.4μg/mL in homozygous variants
[^Citation38]	SLCO1B1	rs4149056 rs2306283	Adult tuberculosis patients 57 study group of 30% are diabetics and 27 validation group of 27% are diabetics	No variation of rifampicin volume of distribution or clearance was observed for both SLCO1B1 gene A388T (rs2306283) and T521C (rs4149056).
	ABCB 1	rs1045642		No effect of rs1045642 SNP on rifampicin pharmacokinetics was observed
[^Citation33]	SLCO1B1	rs4149032	100 tuberculosis patients where 50 are HIV positive	No effect of SLCO1B1 rs4149032 genotype on rifampin Median Cmax and Median AUC0–24 was observed
[^Citation34]	SLCO1B1	rs4149032 rs4149033 rs11045819	256 adult tuberculosis patients from India	No significant difference in 2 hr rifampicin plasma concentration for all SNPs studied was observed
[^Citation39]	SLCO1B1	rs4149056	34 tuberculosis patients of which 41.2% are diabetics and some are taking other drugs	AG genotype of SLCO1B1 388A>G had lower rifampicin AUC0–24 h compared to AA genotype (83.42 mcg.h/mL versus 108.31 mcg.h/mL) respectively
	ABCB 1	rs1045642 (3435C>T)		Patients with CC or CT genotypes showed lower values in Cmax, and AUC0–24 h compared to those with a TT genotype (Cmax = 9.1 6 mcg/mL versus 15.8 6 mcg/mL; AUC0–24 h = 72.83mcg.h/mL versus 130.35 6 29.5 mcg.h/mL respectively)
[^Citation42]	SLCO1B1	rs2306283 rs11045819 rs4149056 rs4149032	113 children aged 3 months to 14 years and 59 (52.2%) were HIV co-infected	In post hoc analysis, the rare SLCO1B1 c.388AA genotype was associated with lower rifampicin Cmax (1.81µg/mL versus 7.11 µg/mL) and AUC0–8h (9.33 µg.h/mL versus 29.50 µg.h/mL) and higher CL/F and V/F compared to those with c.388GG
[^Citation40]	SLCO1B1	rs4149032 rs4149056 rs11045819	60 adult tuberculosis patients aged from 18 to 55 years and 16% were HIV infected.	Patients heterozygous and mutant homozygous for rs4149032 had 18% and 28% reductions in the bioavailability of rifampicin respectively.
	ABCB 1	rs1045642 rs2032582 rs1128503 rs3842		The ABCB1 G2677T (rs2032582) showed no statistically significant increase (19%) in the CL/F and a 19% increase in the mean transit time
[^Citation41]	SLCO1B1	rs2306283 rs4149032	162 pulmonary tuberculosis from two clinical studies receiving rifapentine in South Africa	No effect on oral clearance, apparent volume of distribution, and F was detected
[^Citation37]	SLCO1B1	rs2306283 rs11045819 rs4149056 rs4149032	105 adult patients were newly diagnosed with active pulmonary TB, and Twenty (19%) patients had diabetes mellitus	rs4149032 wild type (TT) had lower oral clearance and higher AUC but no statistically significant differences were detected
[^Citation35]	SLCO1B1	rs4149032 rs2306283	A cohort of 50 HIV negative patients 25 with rifampicin sensitive pulmonary TB and 25 patients with rifampicin-resistant	When adjusted for all covariates no significant effect of the two SLCO1B1 genotypes on rifampicin pharmacokinetics parameters was identified
[^Citation36]	SLCO1B1	rs11045819 rs4149056 rs59502379 rs2306283 rs4149015	72 TB patients (37 from Africa and 35 from the United States and Spain) and 16 healthy controls from USA	Patients with the SLCO1B1 c.463C>A (rs11045819) polymorphism had 42% lower rifampicin AUC0–24, 34% lower Cmax, and 63% CL/F
[^Citation44]	SLCO1B1	rs2239751 rs2306283 rs11045819 rs4149014 rs4149032 rs4149056	173 adults of different races and countries of origin of which 12 are HIV positive	None of the SLCO1B gene polymorphism investigated were associated with rifapentine exposure (AUC 24hour)

Abbreviations: AUC, area under curve; PK, pharmacokinetic; SNP, single nucleotide polymorphism; Cl, clearance; F, bioavailability; Cmax, maximum concentration; CL/F, apparent oral clearance; V/F, apparent predicted volume of distribution.

Table 2 Summary of the Studies Reported the Drug-Metabolizing Enzyme (AADAC and CES) Gene Polymorphisms Association with Rifamycins Pharmacokinetics Variation

Reference	Gene	SNPs	Characteristics of Study Participant	Rifamycins Pharmacokinetics
[^Citation43]	CES 1	rs12149368	174 Malawian adults with pulmonary tuberculosis of which 98 are HIV-infected patients	No associations between rifampicin AUC, Cmax, (CL/F), or V/F and AADAC or CES-1 SNPs polymorphism were identified
	AADAC	rs1803155 rs61733692
[^Citation42]	CES2	rs3759994	113 children aged 3 months to 14 years and 59 (52.2%) were HIV co-infected	No significant effect of studied CES2 SNPs on rifampicin Cmax, AUC, and CL/F was observed
[^Citation41]	AADAC	rs1803155	162 pulmonary tuberculosis patients from two clinical studies receiving rifapentine in South Africa	Patients carrying the AA variant of AADAC rs1803155 were found to have a 10.4% lower rifapentine clearance
[^Citation45]	CES2	c.-2548C>T c.-2263A>G c.269–965A>G c.474–152T>C c.615+120G>A c.1612+136G>A c.1613–87G>A c.1872*69A>G c.1872*302_304delGAA c.1872*445C>T	35 patients with tuberculosis receiving a first-line antituberculosis treatment and 100 healthy individuals for analysis of the frequency of genetic variations in CES2 in the general population	The plasma rifampicin concentration increased with the number of risk alleles at c.2263A>G, c.269–965A>G and c.1612+136G>A, for example for c.2263A>G 8.9 mg/L versus 13.9mg/L for GG and AA respectively, while the plasma concentration decreased along with an increase in the number of risk alleles at c.1872*302_304delGAA
[^Citation44]	AADAC	rs1803155	173 adults of different races and countries of origin of which 12 are HIV positive	Rifapentine exposure (AUC 24) decreased by 10.2% in black participants for AADAC rs1803155 G versus A allele
	CES2	rs8045523 rs8192925 rs4783745		17.2% increase in rifapentine AUC0-24 for rs8192925 G versus A was observed

Abbreviations: AUC, area under the curve; CES, carboxylesterases; AADAC, arylacetamide deacetylase; Cmax, maximum concentration; CL/F, apparent oral clearance; V/F, apparent predicted volume of distribution.

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