Table 3.
Pharmacokinetics of D‐4F in plasma
| Characteristic | 100 mg | 300 mg | 500 mg uncensored | 500 mg after censoring women | |
|---|---|---|---|---|---|
| I. Pharmacokinetics including subjects with undetectable plasma D‐4F treated as zero values | |||||
| A. Plasma D‐4F Cmax, where Cmax = 0 when D‐4F undetectable, ng/mL, mean (95% CI) | |||||
| Day 1 (0–2 h) | Men | 2.37 (1.31–3.43) | 4.43 (1.17–7.69) | 23.39 (6.32–40.45) | 23.39 (6.32–40.45) |
| Women | 4.03 (‐2.55 to 10.61) | 6.86 (3.70–10.02) | 177.98 (‐43.36 to 399.32) | 67.30 (5.05–129.55) | |
| Pooled across interactiona | [2.70 (1.27–4.14)] | [5.40 (3.07–7.74)] | [64.61 (‐0.46 to 129.68)] | [32.80 (12.80–52.79)] | |
| Day 13 (0–8 h) | Men | 2.27 (1.31–3.23) | 5.38 (2.54–8.21) | 33.56 (14.81–52.30) | 33.56 (14.81–52.30) |
| Women | 2.25 (‐0.15 to 4.65) | 10.80 (5.83–15.77) | 196.80 (‐94.21 to 487.80) | 49.06 (7.98–90.15) | |
| Pooled across interactionb | 2.27 (1.40–3.13) | 7.55 (4.68–10.41) | 80.20 (‐5.62 to 166.01) | 37.14 (20.36–53.91) | |
| B. Plasma D‐4F AUC, where AUC = 0 when D‐4F undetectable, ng/mL × hour, mean (95% CI) | |||||
| Day 1 (0–2 h) | Men | 2.82 (1.05–4.60) | 4.56 (1.57–7.54) | 32.94 (7.82–58.07) | 32.94 (7.82–58.07) |
| Women | 6.42 (‐4.15 to 16.98) | 7.00 (3.79–10.21) | 246.59 (‐37.00 to 530.18) | 107.66 (‐4.40 to 219.73) | |
| Pooled across interactiona | [3.54 (1.14–5.93)] | [5.53 (3.31–7.75)] | [89.92 (4.03–175.80)] | [48.95 (16.19–81.72)] | |
| Day 13 (0–8 h) | Men | 6.94 (3.70–10.18) | 22.70 (9.85–35.54) | 104.06 (66.41–141.71) | 104.06 (66.41–141.71) |
| Women | 11.60 (‐2.82 to 26.02) | 47.37 (27.06–67.68) | 522.93 (‐39.03 to 1084.89) | 246.76 (33.16–460.36) | |
| Pooled across interactiona | [7.87 (4.20–11.55)] | [32.57 (20.09–45.04)] | [223.74 (44.56–402.91)] | [136.99 (75.92–198.06)] | |
| II. Pharmacokinetics excluding subjects with undetectable plasma D‐4F | |||||
| A. Excluded population: D‐4F‐exposed subjects with undetectable plasma D‐4F (day 1 5/45 = 11%, day 13 4/44 = 9%) | |||||
| Day 1 (0–2 h) | 3/15 (20%) | 2/15 (13%) | 0/15 (0%) | ||
| Day 13 (0–8 h) | 3/15 (20%) | 1/15 (7%) | 0/14 (0%) | ||
| B. Plasma D‐4F time of events when D‐4F detected on day 13, pooling genders, hours, mean (95% CI) | |||||
| Time of peak | Mean (CI) | 2.25 (1.61–2.89) | 2.39 (1.47–3.31) | 1.65 (0.89–2.42) | |
| Median (range) | 2.00 (1.00–4.00) | 2.00 (0.50–7.92) | 1.27 (0.25–4.02) | ||
| T‐Half | Mean (CI) | 0.81 (0.29–1.32) | 1.18 (0.60–1.77) | 1.99 (1.38–2.60) | |
| Median (range) | 0.46 (0.37–3.04) | 0.45 (0.33–2.95) | 1.88 (0.35–4.83) | ||
| C. Plasma D‐4F Cmax when D‐4F detected, ng/mL, mean (95% CI) | |||||
| Day 1 (0–2 h) | Men | 2.84 (1.81–3.88) | 5.70 (2.01–9.38) | 23.39 (6.32–40.45) | 23.39 (6.32–40.45) |
| Women | 6.05 (‐3.06 to 15.16) | 6.86 (3.70–10.02) | 177.98 (‐43.36 to 399.32) | 67.30 (5.05–129.55) | |
| Pooled across interactiona | [3.38 (1.80–4.95)] | [6.23 (3.85–8.62)] | [64.61 (‐0.46 to 129.68)] | [32.80 (12.80–52.79)] | |
| Day 13 (0–8 h) | Men | 2.72 (1.82–3.63) | 6.05 (3.20–8.89) | 33.56 (14.81–52.30) | 33.56 (14.81–52.30) |
| Women | 3.37 (1.72–5.03) | 10.80 (5.83–15.77) | 196.80 (‐94.21 to 487.80) | 49.06 (7.98–90.15) | |
| Pooled across interactionb | 2.83 (2.04–3.62) | 8.09 (5.22–10.95) | 80.20 (‐5.62 to 166.01) | 37.14 (20.36–53.91) | |
| D. Plasma D‐4F observed AUC when D‐4F detected, ng/mL × hour, mean (95% CI) | |||||
| Day 1 (0–2 h) | Men | 3.38 (1.43–5.34) | 5.86 (2.63–9.09) | 32.94 (7.82–58.07) | 32.94 (7.82–58.07) |
| Women | 9.62 (‐5.08 to 24.33) | 7.00 (3.79–10.21) | 246.59 (‐37.00 to 530.18) | 107.66 (‐4.40 to 219.73) | |
| Pooled across interactiona | [4.42 (1.64–7.21)] | [6.38 (4.17–8.59)] | [89.92 (4.03–175.80)] | [48.95 (16.19–81.72)] | |
| Day 13 (0–8 h) | Men | 8.33 (5.09–11.56) | 25.54 (12.41–38.67) | 104.06 (66.41–141.71) | 104.06 (66.41–141.71) |
| Women | 17.40 (2.03–32.76) | 47.37 (27.06–67.68) | 522.93 (‐39.03 to 1084.89) | 246.76 (33.16–460.36) | |
| Pooled across interactiona | [9.84 (6.00–13.68)] | [34.89 (22.42–47.36)] | [223.74 (44.56–402.91)] | [136.99 (75.92–198.06)] | |
| E. Plasma D‐4F extrapolated AUC when D‐4F detected on day 13, ng/mL × hour, mean (95% CI) | |||||
| Day 13 (0–∞) | Men | 8.47 (4.87–12.08) | 27.24 (12.83–41.66) | 111.07 (71.91–150.22) | 111.07 (71.91–150.22) |
| Women | 19.94 (‐0.40 to 40.28) | 50.21 (28.84–71.59) | 574.85 (12.12–1137.59) | 304.27 (38.08–570.47) | |
| Pooled across interactiona | [10.56 (5.71–15.41)] | [38.73 (24.69–52.77)] | [243.58 (57.54–429.61)] | [155.65 (79.95–231.36)] | |
AUC, area under the curve; CI, confidence interval; Cmax, peak plasma concentration.
Italics indicate a mean that was arrived at by dropping observations from a woman with an extraordinarily robust plasma response to D‐4F, who was considered a biological outlier. Censored means thereby conservatively err on the side of underestimating the effect of D‐4F, especially among women. Significance test for interaction by gender (a.k.a. effect modification): a P < 0.05; b P < 0.1. When interaction is present, the pooled results should be treated with special caution, as results may not be readily generalized to mixed‐gender populations, unless they match the ratio of men to women within the particular group being generalized. Some authorities suggest accepting P < 0.1 as evidence for significant interaction. Pooled results affected by significant effect modification at P < 0.05 are enclosed by brackets. Parameters incorporating time were based on actual times rather than target times.