Table 2. . Characteristics of pharmacokinetics studies of methadone with genotyping available.
| Study (year) | n | Male | Female | Methadone samples | Genotype | Analysis† | Ref. |
|---|---|---|---|---|---|---|---|
| Csajka (2016) | 251 | 190 | 61 | PK modeling 244 peak (C4) and/or trough (C0), seven rich samples (11 each) in steady state |
CYP2B6: *6 [*4 and *9], *5, *11, intronic (rs2279344), intronic (rs8192719) CYP2C9 *2, *3 CYP2C19 *2, *3 CYP2D6 *3, *4, *5, *6 CYP3A4*1B, *22 CYP3A5*3 CYP3QA7*1C ABCB1 61A>G, 1199G>A, 1236C>T, 2677G>T, 3435C>T |
Population PK analysis with genotypes and supposed activity scores as covariates on clearance parameter | [42] |
| Crettol (2005) | 209 | NA | NA | 192 patients with trough (C0) and/or peak (C4) samples in steady state; 17 with trough only |
CYP2B6 *4, *5, *6, *7, *9 CYP2C9 *2, *3 CYP2C19 *2, *3 |
Univariate analysis between genotype and concentrations | [69] |
| Crettol (2006) | 245 | 185 | 60 | 245 trough (C0) and 203 (C4) peak samples under steady state |
CYP1A2*1F CYP2B6*4, *5, *9, CYP2C9*2, *3 CYP2C19*2, *3, CYP2D6*3, *4, *5, *6, xN CYP3A4*1B, *3 ABCB1 61A>G, 2677G>T, 3435C>T UGT2B7*2a |
Univariate analysis between genotype and concentrations | [64] |
| Dennis (2014) Meta-analysis |
NA | NA | NA | Data from four PK studies out of total seven studies selected for review. Crettol et al., Fonseca et al. and Uehlinger et al. |
CYP2B6*6 ABCB1 3435C>T |
Univariate analysis between genotype and concentrations | [64,65,69,72,85] |
| Kharasch (2015) | 64 | NA | NA | 489 genotyped out of which three groups of 20 subjects each were created with CYP2B6*1/*1, CYP2B6*1/*6 and CYP2B6*6/*6. Multiple PK samples through 96 h after single dose in healthy volunteers. | CYP2B6 *4, *5, *6, *7, *9, *16 and *18 | Univariate analysis between plasma EDDP/methadone, AUC ratio and genotype | [66] |
| Bunten (2010) | 67 | NA | NA | Concentration measured during autopsy | CYP2B6 *6 (*4 and *9) | Univariate analysis between genotype and concentrations | [68] |
| Kringen (2017) | 64 | NA | NA | At steady state (≥12 h after last intake of methadone) |
CYP2B6 *6 (*4 and *9) CYP3A5 *3 CYP2C9 *2, *3 CYP2D6 *3, *4, *5, *6 CYP2C19 *2, *3 |
Linear mixed model analysis along with age, gender and time with repeated measurements of concentration | [67] |
| Wang (2011) | 366 | 297 | 69 | Trough samples at steady state | rs8100458, rs10500282, rs10403955, rs2279342, rs3745274 (*9), rs2279343 (*4) rs2279345, rs1038376, rs707265, rs1042389 |
Univariate analysis between identified genotype and concentrations after multiple testing correction | [70] |
| Fonseca (2017) | 105 | 74 | 31 | 76 responders and 29 nonresponders. Trough samples at steady state |
CYP2B6 *1, *4, *6 CYP2C19 *1, *2, *3 CYP2D6 *1, *2, *3, *4, *5, *6, *9, *10, *17, *35, *41 CYP3A5 *1*3 CYP2C9 *1*2*3 ABCB1 3435C>T |
Univariate analysis between genotype and concentrations after multiple testing correction | [72] |
| Bart (2014) | 206 | NA | NA | PK modeling with 441 samples at steady state |
CYP3A4 *1b, rs28371759, rs4986909 CYP2B6*4, *5, *9, intronic (rs8192709) CYP2D6 rs1065852, rs5030656 CYP2C19 rs3758581 ABCB1 61A>G, 1236C>T, 2677G>T, 3435C>T, rs6949448, rs2235067, rs1922242, rs1128503, rs2520464, rs3789243 CYP1A2 rs762551 |
Population PK analysis with genotypes as covariates on clearance parameter | [71] |
| Ahmad (2017) | 228 | NA | NA | Concentration measured during autopsy compared with 297 controls |
CYP2B6 *5, *9, *2, *8, *15 intronic (rs2279344, rs4803419, rs8192719) |
Univariate analysis between genotype and concentrations after multiple testing correction | [73] |
| Dobrinas (2013) | 276 | NA | NA | Trough samples at steady state | CYP2B6 sequencing of 3917 bp including all nine exons and exon–intron boundaries | Univariate analysis between identified genotype and concentrations after multiple testing correction | [74] |
| Yang (2016) | 344 + 76 | 281 + 59 | 63 + 17 | At steady state. Sampling schedule unknown. Genotyping in 344 patients to identify susceptibility loci. Additional 76 patients used for validation. |
Whole-genome pharmacogenomic study using Axiom Genome-Wide CHB 1 Array (Affymetrix, CA, usa) | Genome-wide singe-locus association analysis after multiple test correction and sliding-window haplotype-based association analysis with concentration | [75] |
| Wang (2013) | 366 | NA | NA | Samples at 24 ± 2 h after the last methadone dose at steady state | CYP2C19 *2, *3 | Univariate analysis between genotype and concentrations | [76] |
| Carlquist (2015) | 31 | NA | NA | Day 1 and day 21 peak and trough concentrations |
CYP2B6 *9 CYP3A4 *1b, *22 CYP2C19 *2 ABCB1 3435C>T NOS1AP (rs12143842) |
Univariate analysis between genotype and concentrations | [50] |
| Richards (2014) | 228 | NA | NA | Concentration measured during autopsy |
CYP3A4 *1B rs4987161, rs4986910 intronic (rs2246709, rs3735451, rs4646437 and rs2242480) |
Univariate analysis between genotype and concentrations | [77] |
| Eap (2001) | 256 | 202 | 54 | Plasma trough at steady state. 15 patients with bd dosing were removed from analysis | CYP2D6*3, *4, *5, *6, *xN | Univariate analysis between genotype and concentrations after multiple testing correction | [78] |
| Lee (2013) | 178 | 156 | 22 | Plasma trough at steady state | CYP2B6 *4, *9, and *5, CYP2C19 *2, *3, *17 and ABCB1 1236C>T, 2677G>T/A and 3435C>T | Univariate analysis between genotype and concentrations | [79] |
| Barratt (2012) | 119 | NA | NA | Plasma trough at steady state | ABCB1 61A>G, 1199G>A, 1236C>T and 3435C>T | Univariate analysis between genotype and concentrations without multiple testing correction | [27] |
| Zahari (2016) | 148 | 148 | NA | Trough, 0.5, 1, 2, 4, 8, 12 and 24 h after morning dose at steady state | ABCB1 1236C>T, 2677G>T/A and 3435C>T | Univariate analysis between genotype and concentrations without multiple testing correction | [80] |
| Uehlinger (2007) | 14 | NA | NA | Trough samples at steady state before and after >1 week of quetiapine |
CYP2B6 *4, *5, *6, *7, *9 CYP3A5 *3 CYP2D6 *3, *4, *5, *6, *xN ABCB1 3435C>T |
Univariate analysis between before and after concentrations in each of the genotypes | [85] |
†
As mentioned in the published literature.
AUC: Area under the curve; bp: Base pair; EDDP: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; NA: Not available; PK: Pharmacokinetic.