Pharmacokinetic effects influence the evolutionary dynamics of resistance.

<p>Here we consider a baseline mutation rate per cell division of 10⁻⁸ and the effect of drug concentration on the mutation rate <i>β</i> = 10⁻⁹. (A) The drug concentration <i>in vivo</i> based on the pharmacokinetic model over time for a 100mg per day continuous dosing regime. Dotted line: loading dose; solid line: no loading dose. (B) The birth rates as a function of time <i>t</i>. Red line: the birth rate of the resistant cells; black line: the birth rate of the sensitive cells. (C) The mutation rate of sensitive cells as a function of time <i>t</i>. Blue line: constant mutation rate; green line: mutation rate monotonically decreases with the drug concentration; black line: mutation rate monotonically increases with the drug concentration. (D) The probability of resistance as a function of time <i>t</i>. Values for birth and death rates: <i>μ</i>_{<i>X</i>_<i>s</i>}(<i>t</i>) ≈ 0.005 <i>hour</i>⁻¹, <i>μ</i>_{<i>X</i>_<i>r</i>}(<i>t</i>) ≈ 0.002 <i>hour</i>⁻¹, <i>λ</i>_{<i>X</i>_<i>s</i>}(<i>t</i>) ≈ <i>exp</i>(−4.4 ⋅ <i>C</i>(<i>t</i>)−3.17) <i>hour</i>⁻¹, and <i>λ</i>_{<i>X</i>_<i>r</i>}(<i>t</i>) ≈ −0.001 ⋅ <i>C</i>(<i>t</i>) + 0.03 <i>hour</i>⁻¹.