Based on the phenytoin dosing work of Marshall Pierce, PharmD, at pkineticdrugdosing.com.
Units. Every field has its own unit; click the unit to switch it, and the value converts. CA, US and UK set every field and the results to that country's usual units. The model runs in mg/L, g/dL, inches and kg. Phenytoin µmol/L = mg/L × 3.964 (MW 252.27): 10–20 mg/L is 40–80 µmol/L, free 1–2 mg/L is 4–8 µmol/L. Valproic acid µmol/L = mg/L × 6.934. Albumin g/L ÷ 10 = g/dL. Km stays in mg/L.
Salt factor. S = 0.92 for phenytoin sodium capsules, IV phenytoin and fosphenytoin (mg PE); S = 1.0 for chewable tablets and suspension. F = 1. Products are not interchangeable mg for mg.
Binding (Winter Eq 14.2, 14.3, 14.8), applied when albumin is below 44 g/L (4.4 g/dL) or on dialysis: CNB = C / (0.9 × Alb/4.4 + 0.1); hemodialysis C / (0.9 × 0.48 × Alb/4.4 + 0.1); free level free / 0.1; valproate > 20 mg/L (0.095 + 0.001 × VPA) × C / 0.1. Patient-specific reported range is 10–20 mg/L × the binding factor (Eq 14.4–14.7).
Weights and volume. IBW (Devine) 50 (M) or 45.5 (F) + 2.3 kg per inch over 60 (actual weight under 152 cm). Vd = 0.65 L/kg (1 L/kg under 1 year); above IBW, IBW + 1.33(TBW − IBW). Vmax per kg uses the lesser of IBW and actual weight.
Population values (Murphy 2005, from your workbook): 0.5–3 y Km 6.6 (SD 4.2), Vmax 14 (4.2); 4–6 y 6.8 (3.5), 10.9 (3); 7–9 y 6.5 (3), 10.1 (2.6); 10–17 y 5.7 (2.7), 8.3 (2.8); 18–59 y 4.3 (3.5), 7 (3); ≥ 60 y 5.8 (2.3), 7 (3). Winter assumes Km 4 for adults. CYP2C9 intermediate and poor metabolizers: Vmax × 0.75 and × 0.5.
One level (Eq 14.30–14.31): Vmax = R(Km + C)/C, R = S·F·Dose·24/τ; dose Vmax·T/((Km + T)·S); Css = Km·R/(Vmax − R). Two steady-state levels (Eq 14.36): Km = (R2 − R1)/(R1/C1 − R2/C2). Not at steady state: mass balance (Eq 14.33–14.34) eliminated/day = R − (C2 − C1)·V/t, Vmax = eliminated × (Km + Cavg)/Cavg; or a Bayesian fit minimizing ((C2 − C2pred)/(0.1·C2))² + ((Km − Kmpop)/SD)² + ((Vmax − Vmaxpop)/SD)². After stopping (Eq 14.25): Vmax = V·[Km·ln(C1/C2) + (C1 − C2)]/t.
Loading (Eq 14.28, 14.32, 14.29): LD = V·(Cdesired − Cobserved)/S; after IV C0 = S·LD/V; oral peak about 0.5·S·LD/V. Binding does not change the loading dose. Maximum IV rates: phenytoin 50 mg/min (25 elderly or cardiac; children 1 mg/kg/min), fosphenytoin 150 mg PE/min (children 3 mg PE/kg/min). Oral loads: ≤ 400 mg per dose every 2 h. Sample 2 h after IV phenytoin, 4 h after fosphenytoin, 24 h after an oral load. Switch (Eq 14.35): new dose = dose × Sold/Snew. CRRT (Eq 14.38): removed mg/day = unbound level × effluent L/h × 24.
Timing and rounding. Steady-state check (Eq 14.24) (115 + 35C)·C/(R × 70/wt) days; t90 (Eq 14.23); time between levels integrates V·dC/dt = R − Vmax·C/(Km + C). Recheck day 3 (dose ≥ 85% of Vmax, > 15% increase, or predicted > 18 mg/L) or day 5, then at the model's 90% time (≥ day 7). Doses round to 100 + 30 mg capsule combinations (≤ two 30 mg per dose, doses within 30 mg), whole 50 mg chewables, or 25 mg steps, choosing the predicted level closest to target within 10–20 mg/L.
Not modeled. Interacting drugs, enteral feeds, hepatic disease, pregnancy, neonates.
Based on. Marshall Pierce, PharmD. Pharmacokinetic Drug Dosing: pkineticdrugdosing.com, including the phenytoin dosing page and its Phenytoin_Dosing.xlsx and PhenytoinexplicitequationSolving.xlsm calculators. This tool reimplements those methods; any errors are its own.
Other sources. Winter ME. Basic Clinical Pharmacokinetics, 6th ed., ch. 14 (Phenytoin). Tang S, Xiao Y. J Pharmacokinet Pharmacodyn 2007;34:807–827. Goličnik M. Eur J Drug Metab Pharmacokinet 2011;36:121–127. Murphy JE. Clinical Pharmacokinetics, 2005 (population Km and Vmax).