Fig 1.
Lean mass response to 5-FU chemotherapy administration estimated from experimental data [37] following either a daily schedule (A) or a 5-on, 2-off schedule (B) over days (0, 27).
Table 1.
Model parameters and their estimated values from previous data fitting reported in the cited reference.
Fig 2.
Model simulation of plasma and tissue concentrations of 5-FU given (A) one dose, (B) a sequence of 28 daily doses, and (D) a sequence of 20 doses following the (5-on, 2-off) schedule.
The dose of 35 mg/kg was simulated by numerically solving Eqs (1) and (2). The 5-day average exposure for (C) the daily schedule and (E) the (5-on, 2-off) schedule was computed from Eq (9) for τ = 5.
Fig 3.
Model simulation with fitted parameters Rd and τ for the (left) daily and (right) (5-on, 2-off) chemotherapy schedules administering various doses over days (0, 27). Model simulation of lean mass response to chemotherapy for (A) daily and (D) (5-on, 2-off) dosing schedules. Model predicted stem cell ratio (B and E) and average exposure function yτ(t) (C and F), for the daily or (5-on, 2-off) dosing schedules, respectively.
Fig 4.
The sum of squared errors (SSE) (A) and best-fit Rd value (B) for all tested values of τ over [1, 15] and both dosing schedules. From (A), the SSE is minimum when τ = 11 for the daily schedule and τ = 5 in the (5-on, 2-off) schedule. Hence we take the optimal value as the mid-point at τ = 8. From (B), when τ = 8, the approximate average of the two fitted Rd values is Rd = 6.8.
Fig 5.
Parameter sensitivity analysis for parameter Rd using a 35 mg/kg daily (Left: A, B, C) or 49 mg/kg (5-on, 2-off) (Right: D, E, F) chemotherapy schedule to deliver a 245 mg/kg weekly dose. The nominal value is Rd = 6.8. In (A) and (D), The value of Rd is increased or decreased by 10% and the resulting lean mass is shown. The sensitivity coefficients (B and E) and relative sensitivity coefficients (C and F) are computed with a 0.001% change to the nominal value. Chemotherapy is applied over the first 28 days.
Fig 6.
Parameter sensitivity analysis for parameter τ using a 35 mg/kg daily (Left: A, B, C) or 49 mg/kg (5-on, 2-off) (Right: D, E, F) chemotherapy schedule to deliver a 245 mg/kg weekly dose. The nominal value is τ = 8. In (A) and (D) the value of τ is increased or decreased by 10% and the resulting lean mass is shown. The sensitivity coefficients (B and E) and relative sensitivity coefficients (C and F) are computed with a 0.001% change to the nominal value. Chemotherapy is applied over the first 28 days.
Table 2.
Weekly dosing schedules delivering between 168–175 mg/kg/week with equal sized doses.
Fig 7.
Lean mass (A) and tumour (B) response to treatment schedules listed in Table 2. Treatment effect is computed as the fraction of treated lean mass / initial lean mass (C), and treated tumour volume / initial tumour volume (D). Instantaneous therapeutic efficacy is computed by the ratio of the treatment effect fractions (E).
Fig 8.
Treatment efficacy for the weekly dose-equivalent chemotherapy schedules listed in Table 2.
(A) The AUC ratio for lean mass compares the tested schedule to the 24 mg/kg daily schedule. (B) The AUC ratio for tumour volume compares the tested schedule to the 24 mg/kg daily schedule. (C) The total therapeutic efficacy is the ratio of the lean mass AUC ratio to the tumour volume AUC ratio.
Fig 9.
Treatment efficacy for the chemotherapy dosing schedules tested experimentally in [37].
(A) The AUC ratio for lean mass compares the lean mass response from the tested schedule to that of the 24 mg/kg daily schedule. (B) The AUC ratio for tumour volume compares the tumour volume response from the tested schedule to that of the 24 mg/kg daily schedule. (C) The total therapeutic efficacy is the ratio of the lean mass AUC ratio to the tumour volume AUC ratio. If a bar’s height goes above the plot, the height value is written at the top of the bar.
Table 3.
Dosing schedules that deliver a weekly dose of between 168–175 mg/kg/week.
Notation: a schedule described as (4, 1, 1, 1) is a shortening of (4-on, 1-off, 1-on, 1-off), and means doses are given on days 1, 2, 3, 4, and 6 of every week.
Fig 10.
Treatment efficacy for the chemotherapy dosing schedules listed in Table 3.
(A) The AUC ratio for lean mass compares the lean mass response from the tested schedule to that of the 24 mg/kg daily schedule. (B) The AUC ratio for tumour volume compares tumour volume response from the tested schedule to that of the 24 mg/kg daily schedule. (C) The total therapeutic efficacy is the ratio of the lean mass AUC ratio to the tumour volume AUC ratio.
Fig 11.
Treatment efficacy for metronomic chemotherapy schedules administering 168 mg/kg/week over 1, 2, 3, 4, 5, or 6 equal, and equally spaced, daily doses.
Treatment efficacy is measured against the 24 mg/kg daily regime and the 35 mg/kg (5-on, 2-off) regime is included for reference. (A) The AUC ratio for lean mass compares the lean mass response from the tested schedule to that of the 24 mg/kg daily schedule. (B) The AUC ratio for tumour volume compares tumour volume response from the tested schedule to that of the 24 mg/kg daily schedule. (C) The total therapeutic efficacy is the ratio of the lean mass AUC ratio to the tumour volume AUC ratio.
Fig 12.
Comparison of chemotherapy effect on lean mass in a young (6 weeks old, solid lines) and old (2 years old, dashed lines) simulated host.
Predicted lean mass response to treatment (A) and the resulting stem cell ratio (B). Treatment effect on lean mass (C) defined as the ratio of treated lean mass to initial lean mass. Treatment effect on tumour volume (D) defined as the ratio of treated tumour volume to initial tumour volume. Therapeutic efficacy (E) defined as the ratio of the treatment effect on lean mass to the treatment effect on tumour volume.
Fig 13.
Treatment efficacy for young (6 weeks, green-purple bars) and old (2 years, red-orange bars) simulated hosts exposed to chemotherapy schedules administering 168 mg/kg/week in 1, 2, 3, or 4 doses per week, as well as a 3-times a day schedule and an every-other-day schedule.
Treatment efficacy is measured against the 24 mg/kg daily regime and the 35 mg/kg (5-on, 2-off) regime is included for reference. (A) The AUC ratio for lean mass compares the lean mass response from the tested schedule to that of the 24 mg/kg daily schedule. (B) The AUC ratio for tumour volume compares tumour volume response from the tested schedule to that of the 24 mg/kg daily schedule. (C) The total therapeutic efficacy is the ratio of the lean mass AUC ratio to the tumour volume AUC ratio.
Fig 14.
Drug concentration in plasma and tissue model compartments (A) and the average exposure function with τ = 8 (B).
Solid lines are control (no morphine) and dashed lines are with morphine where model parameters k21, k12, and k10 were reduced by 35%.
Fig 15.
Model simulation of various 5-FU dosing schedules with and without adjuvant morphine administration.
Lean mass (A) and tumour volume (B) response to various 5-FU schedules with (dashed lines) and without (solid lines) morphine. Treatment efficacy without (green-purple bars) and with (red-orange bars) morphine for chemotherapy schedules administering 168 mg/kg/week in 1, 2, 3, or 4 doses per week, as well as a 3-times a day schedule, and an every-other-day schedule. Treatment efficacy is measured against the 24 mg/kg daily regime, and the 35 mg/kg (5-on, 2-off) regime is included for reference. (C) The AUC ratio for lean mass compares the lean mass response from the tested schedule to that of the 24 mg/kg daily schedule. (D) The AUC ratio for tumour volume compares tumour volume response from the tested schedule to that of the 24 mg/kg daily schedule. (E) The total therapeutic efficacy is the ratio of the lean mass AUC ratio to the tumour volume AUC ratio.