Table 4.
Effects of variant allele at ABCG2 421C>A (vs. wild type homozygosity) on measured and dose‐adjusted steady‐state lamotrigine troughs: main analysis. Modelsa were fitted to log‐transformed troughs: unadjusted, fully adjusted with treatment–ABCG2 genotype interaction and a parsimonious model (only adjustments with P < 0.1). Effects are geometric means ratios (GMR) with 95% confidence intervals (CI). For the interaction term, GMR is a relative difference in the effect of variant allele between lamotrigine (LAM) + valproate (VAL)‐treated patients and LAM‐only patients, i.e. a difference in the effect of VAL between variant allele carriers and wild type homozygotes
| Measured troughs | Dose‐adjusted troughs | |
|---|---|---|
| Models and effects | GMR (95% CI) | GMR (95% CI) |
| Unadjusted model | ||
| Treatment (LAM + VAL vs. LAM) | 3.57 (2.80–4.54) | 3.10 (2.45–3.93) |
| ABCG2 genotype (variant allele vs. wild type) | 1.13 (0.89–1.43) | 1.13 (0.89–1.42) |
| Treatment*ABCG2 genotype interaction | 2.19 (1.35–3.54)b | 1.89 (1.18–3.03)c |
| LAM + VAL vs. LAM at wild type | 2.41 (1.99–2.92) | 2.26 (1.87–2.73) |
| LAM + VAL vs. LAM at variant allele | 5.28 (3.39–8.20) | 4.26 (2.76–6.57) |
| Variant allele vs. wild type at LAM | 0.76 (0.59–0.98) | 0.82 (0.64–1.05) |
| Variant allele vs. wild type at LAM + VAL | 1.67 (1.11–2.52) | 1.55 (1.04–2.31) |
| LAM daily dose (by 25 mg) | 1.16 (1.13–1.19) | ‐ |
| Fully adjusted + treatment*ABCG2 interaction | ||
| Age (by 5 years) | 0.99 (0.95–1.02) | 0.99 (0.96–1.03) |
| Sex (men vs. women) | 0.94 (0.77–1.13) | 1.03 (0.85–1.23) |
| Body mass index (by 2 kg m b) | 0.96 (0.91–1.00) | 0.95 (0.91–0.99) |
| Treatment (LAM + VAL vs. LAM) | 3.49 (2.73–4.44) | 3.02 (2.38–3.83) |
| UGT1A4*3 142T>G (variant allele vs. wild type) | 0.94 (0.79–1.14) | 0.90 (0.74–1.10) |
| UGT2B7 –161C>T (variant allele vs. wild type) | 0.97 (0.80–1.19) | 0.97 (0.80–1.19) |
| MDR1 exon 12 1236C>T (variant vs. wild type) | 1.06 (0.89–1.27) | 1.03 (0.86–1.22) |
| ABCG2 421C>A (variant allele vs. wild type) | 1.14 (0.89–1.45) | 1.14 (0.90–1.45) |
| Treatment*ABCG2 421C>A interaction | 2.36 (1.39–3.64)b | 1.97 (1.22–3.18)c |
| LAM + VAL vs. LAM at wild type | 2.32 (1.89–2.83) | 2.15 (1.77–2.62) |
| LAM + VAL vs. LAM at variant allele | 5.24 (3.38–8.15) | 4.24 (2.75–6.54) |
| Variant allele vs. wild type at LAM | 0.76 (0.59–0.98) | 0.81 (0.63–1.04) |
| Variant allele vs. wild type at LAM + VAL | 1.72 (1.14–2.62) | 1.60 (1.07–2.62) |
| LAM daily dose (by 25 mg) | 1.16 (1.13–1.19) | ‐ |
| Parsimonious model | ||
| Body mass index (by 2 kg m b) | 0.95 (0.91–0.99) | 0.95 (0.92–0.99) |
| Treatment (LAM + VAL vs. LAM) | 3.50 (2.75–4.44) | 3.05 (2.41–3.85) |
| ABCG2 genotype (variant allele vs. wild type) | 1.13 (0.89–1.43) | 1.13 (0.89–1.42) |
| Treatment*ABCG2 genotype interaction | 2.29 (1.43–3.70)b | 1.98 (1.24–3.16)c |
| LAM + VAL vs. LAM at wild type | 2.31 (1.90–2.80) | 2.17 (1.80–2.62) |
| LAM + VAL vs. LAM at variant allele | 5.30 (3.43–8.20) | 4.29 (2.79–6.58) |
| Variant allele vs. wild type at LAM | 0.74 (0.58–0.96) | 0.80 (0.62–1.03) |
| Variant allele vs. wild type at LAM + VAL | 1.71 (1.14–2.55) | 1.58 (1.06–2.35) |
| LAM daily dose (by 25 mg) | 1.16 (1.13–1.19) | ‐ |
Unadjusted and fully adjusted with treatment–genotype interaction are models described in Table 3 used for the analysis of other polymorphisms
P = 0.001 in the unadjusted, P = 0.001 in the fully adjusted and P < 0.001 in the parsimonious model
P = 0.009 in the unadjusted, P = 0.006 in the fully adjusted and P = 0.005 in the parsimonious model