Table 1.
Summary of studies assessing the impact of genetic polymorphisms on phenytoin pharmacokinetics and/or clinical outcomes
| Study, year | Country/study population | PHT dosing regimen | Genotype(s)/reported allelic frequencies percentage | Pharmacokinetic outcomes | ||||
|---|---|---|---|---|---|---|---|---|
| Aynacioglu et al. [42] | Turkey Outpatients (n = 280); healthy volunteers (n = 218) PHT PK analysis in healthy volunteer subgroup (n = 101) |
300 mg PO × 1 Sample collected 12-h post-dose |
CYP2C9
Study population *1 = 79.4 *2 = 10.6 *3 = 10 Population included in PHT PK analysis: *1 = 81.7 *2 = 9.4 *3 = 8.9 |
Genotype | Serum PHT, mean mg/L (95% CI) | |||
| CYP2C9*1/*1 CYP2C9*1/*2 CYP2C9*1/*3 CYP2C9*2/*2 CYP2C9*2/*3 CYP2C9*3/*3 |
4.16 (3.86–4.46) 5.52 (4.66–6.39) 5.65 (4.86–6.43) 6.58 (1.64–11.51) Not observed 5.92a |
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| Genotype | p-HPPH/PHT ratio (95% CI) | |||||||
| CYP2C9*1/*1 CYP2C9*1/*2 CYP2C9*1/*3 CYP2C9*2/*2 CYP2C9*2/*3 CYP2C9*3/*3 |
0.43 (0.39–0.47) 0.26 (0.21–0.31) 0.21 (0.18–0.24) 0.14 (0.13–0.14) Not observed 0.02a |
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| Kerb et al. [43] | Turkey Healthy volunteers (n = 96) |
300 mg PO × 1 Sample collected 12-h post-dose |
CYP2C9
*1 = 81.3 *2 = 10.1 *3 = 8.8 CYP2C19 *1 = 88.3 *2 = 11.7 MDR1 (ABCB1) C3435T C = 52.6 T = 47.4 |
Genotype | Serum PHT, mean mg/L ± SD | |||
| CYP2C9*1/*1 CYP2C9*1/*2 CYP2C9*1/*3 CYP2C9*2/*2 CYP2C9*2/*3 CYP2C9*3/*3 CYP2C19*1/*1 CYP2C19*1/*2 CYP2C91*2/*2 MDR1 CC MDR1 CT MDR1 TT |
4.20 ± 1.25 5.52 ± 1.43 5.54 ± 1.47 6.58 ± 1.99 Not observed 5.92a 4.73 ± 1.47 4.49 ± 1.68 4.40 ± 1.41 4.27 ± 1.74 4.85 ± 1.33 4.87 ± 1.36 |
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| Multiple linear regression indicates the number of polymorphic CYP2C9 alleles and MDR1*T alleles account for 14.1 and 1.3% of the variability in phenytoin serum concentrations, respectively (r 2 = 0.154, p = 0.0002) | ||||||||
| Ozkaynakci et al. [44] | Turkey Epilepsy clinic outpatients taking PHT mono- or polytherapy (n = 101) Seizure etiology: epilepsy, brain tumor, glioma, head trauma, or AVM Polytherapy, mostly CBZ, LTG, or VPA |
Mean dose 4.1 mg/kg/day PO Mean duration 96.6 weeks (≥7 days) C tr collected pre-dose |
CYP2C9
*1 = 89.2 *2 = 7.4 *3 = 3.4 CYP2C19 *1 = 70.1 *2 = 19.6 *3 = 10.3 |
Genotype group (CYP2C9, 2C19) | Serum PHT C tr, mean mg/L (SEM) | |||
| *1/*1, *1/*1 *1/*1, *1/*2 *1/*1, *1/*3 *1/*1, *2/*2 *1/*1, *2/*3 *1/*2, *1/*1 *1/*2, *1/*2 *1/*2, *1/*3 *1/*3, *1/*1 *1/*3, *1/*3 *1/*3, *2/*3* |
7.43 (0.73)†
9.16 (1.46)*** 7.51 (2.56)*** 9.80 (4.52)** 10.35 (2.29)*** 8.90 (1.30)† 14.80 (2.90) 16.20* 10.47 (4.68) 10 (1.20) 27.90 (1.85) |
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| *Reference genotype group for all comparisons: ** p < 0.05, *** p < 0.005, † p < 0.001 | ||||||||
| Alhazzani et al. [45] | Saudi Arabia Epileptic patients taking PHT monotherapy: drug responsive (n = 25), drug resistant (n = 25) |
300 mg PO daily ≥1 month Multiple samples collected over 12 h following dose |
MDR1 (ABCB1) C3435T
Drug responsive C = 88 T = 12 Drug resistant C = 70 T = 30 |
PK parametersb | Genotype | |||
| CC | CT | TT | ||||||
|
C
max (mg/mL) T max (h) AUC0–12h (mg h/mL) t½ (h) Cl (L/h) |
20.4 (0.29) 6 (0.12) 302 (0.45) 19.2 (0.36) 0.8 (0.11) |
28 (0.10) 6 (0.08) 545 (0.71) 30.2 (0.12) 0.5 (0.04) |
32 (0.16) 6 (0.08) 631 (0.48) 33.3 (0.4) 0.42 (0.21) |
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| Ebid et al. [46] | Egypt Epilepsy clinic outpatients taking PHT for partial (n = 43) or generalized tonic-clonic (n = 57) seizures; healthy volunteers from blood bank unit (n = 50) PHT phenotyping in epilepsy patients (n = 100) |
Baseline dose 100 mg PO BID ≥1 year Dose adjustment at 3 months: if drug resistant and C tr <10 mg/L: 150 mg PO TID If drug resistant and C tr 10–14 mg/L: 100 mg PO TID If drug responsive and/or C tr ≥15 mg/L: stop PHT and end follow-up C tr collected pre-dose |
MDR1 (ABCB1) C3435T
Drug responsive C = 36.5 T = 63.5 Drug resistant C = 74.6 T = 25.4 Healthy volunteers C = 48 T = 52 |
3-month evaluation (n = 100) | ||||
| Responsive, n = 18 (%) | Resistant, n = 82 (%) | |||||||
| Serum PHT C
tr, mg/L <10 10 to <15 ≥15 |
50 44.4 6.7 |
79.3 17.1 3.7 |
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| Genotype CC CT TT |
0 44.4 55.6 |
48.8 40.2 11 |
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| 6-month evaluation (n = 79) | ||||||||
| Responsive, n = 19 (%) | Resistant, n = 60 (%) | |||||||
| Serum PHT C
tr, mg/L <10 10 to <15 ≥15 |
10.5 31.6 57.9 |
15 68.3 16.7 |
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| Genotype CC CT TT |
26.3 47.4 26.3 |
58.3 36.7 5 |
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AUC 0–12h area under the concentration–time curve from 0 to 12 h post-dose, AVM arteriovenous malformation, BID twice daily, CBZ carbamazepine, CI confidence interval, Cl clearance, C max maximum plasma concentration, C tr trough concentration, CYP cytochrome P450, LTG lamotrigine, PHT phenytoin, p-HPPH 5-(p-hydroxyphenyl)-5-phenylhydantoin metabolite, PK pharmacokinetic, PO orally by mouth, SD standard deviation, SEM standard error of the mean, t½ half-life, TID three times daily, T max time to C max, VPA valproic acid
aFrom one individual, cannot calculate 95% CI, SD, or SEM
bMean (SEM) reported