Blood Concentration Profiles of Two Antimalarials with Different Elimination Profiles

<p>The examples shown here are mefloquine (orange) and chloroquine (pink). An increase in MIC has different effects on the shortening of post-treatment suppressive prophylaxis (hatched bars). MIC_R, MIC for resistant parasites; MIC_S, MIC for sensitive parasites.</p

In Vivo Antimalarial Pharmacodynamics

<p>The parasite burden in an adult (vertical axis) is shown in green. After parasite burden expands to the point where it causes illness, treatment is given (red arrow), which causes a log-linear decline in parasite numbers until concentrations of the antimalarial drug (grey shading) fall below the MPC. As the antimalarial blood levels fall further, the decline in parasite burden slows until it reaches a multiplication rate of one (the antimalarial concentration at this point is the in vivo MIC). The parasite population then expands to cause a recrudescence six weeks later. The sigmoid concentration–effect relationship is shown in brown; it is depicted in the reverse direction to that normally drawn. PMR, parasite multiplication rate.</p

Post treatment prophylaxis following a slowly eliminated antimalarial such as chloroquine or piperaquine in a high transmission setting (left figure) where the EIR is 1000/year and in a low transmission setting where the EIR is 1/year

<p><b>Copyright information:</b></p><p>Taken from "How antimalarial drug resistance affects post-treatment prophylaxis"</p><p>Malaria Journal 2008;7():9-9.</p><p>Published online 11 Jan 2008</p><p>PMCID:PMC2254426.</p><p></p> The drug concentrations are shown in red and the vertical bars represent cumulative incidence of reinfection; tand tare the times to reach a 20% and 50% cumulative incidence of reinfection

In this diagram a slowly eliminated drug given over three days has a single component (monoexponential) elimination phase with a half-life of 5

<p><b>Copyright information:</b></p><p>Taken from "How antimalarial drug resistance affects post-treatment prophylaxis"</p><p>http://www.malariajournal.com/content/7/1/9</p><p>Malaria Journal 2008;7():9-9.</p><p>Published online 11 Jan 2008</p><p>PMCID:PMC2254426.</p><p></p>5 days. This corresponds with a one-compartment model. The vertical axis has a logarithmic scale. The in-vivo MIC is 1.25 μmol/L. Each doubling of MIC shortens the PTP by one half-life

Relationship between MIC and PTP

<p>The proportional increase in malaria parasite MIC with resistance is plotted against the shortening of the duration of PTP, expressed as multiples of the terminal half-life. This applies only to drugs for which suppressive antimalarial prophylaxis occurs in the terminal elimination phase (i.e., most drugs).</p

Three levels of antimalarial susceptibility for a slowly eliminated antimalarial with a multiphasic elimination profile (e

<p><b>Copyright information:</b></p><p>Taken from "How antimalarial drug resistance affects post-treatment prophylaxis"</p><p>http://www.malariajournal.com/content/7/1/9</p><p>Malaria Journal 2008;7():9-9.</p><p>Published online 11 Jan 2008</p><p>PMCID:PMC2254426.</p><p></p>g chloroquine, piperaquine) are shown reflected by the respective minimum inhibitory concentrations (MIC); sensitive (S), resistant (R) and highly resistant (HR). Post treatment prophylaxis for sensitive parasites is six weeks. In this example increasing levels of resistance progressively shorten the PTP from six to three weeks (a) and then from three to two weeks (b)

Hypothetical Parasite Burden Profiles during Pregnancy with SP IPT in a High-Transmission Setting

<p>Entomological inoculation rate is about 50 infectious bites per person per year. Note that many infections self-cure (each infection is depicted as a green line). The hatched bars represent the duration of “suppressive prophylactic activity”, and the solid bars represent the period during which parasite multiplication is suppressed (i.e., levels exceed the in vivo MIC). The horizontal dotted line at 10⁸ parasites represents the level at which malaria can be detected on a blood film. (A) represents a drug-sensitive area; (B) represents a moderately resistant area.</p

Worsening resistance; the antimalarial concentration-effect relationship moves to the right

<p><b>Copyright information:</b></p><p>Taken from "How antimalarial drug resistance affects post-treatment prophylaxis"</p><p>http://www.malariajournal.com/content/7/1/9</p><p>Malaria Journal 2008;7():9-9.</p><p>Published online 11 Jan 2008</p><p>PMCID:PMC2254426.</p><p></p> In this example the shift is parallel. IC50 is the concentration giving 50% of maximum effect, and Emax is the maximum effect possible. Usually in-vitro susceptibility is assessed by growth inhibition, inhibition of uptake of H Hypoxanthine, or inhibition of formation of pLDH or PfHRP2

Simplified Outline of the Iterative Process of the Clinical Development of New Antimalarial Candidate Drugs or Drug Combinations

<p>Phase III trials are designed to provide pivotal efficacy and safety data for obtaining regulatory approval. The indicated numbers of study participants are approximations of the magnitude of required total sample sizes in different transmission settings.</p

Simulated Plots of Weekly Incidence Rates and Cumulative Proportions for Recrudescent Primary Infections and Re-Infections Following Treatment of Uncomplicated P. falciparum Malaria with a Slowly Eliminated (Partner) Drug (Half-Life of ~1 Week)

<p>The solid line represents recrudescent infections with a cumulative failure rate of 5% by day 42. Dashed lines represent different rates of re-infections corresponding to entomological inoculation rates of two (yellow), four (orange), and six (red) infective mosquito bites/year, respectively. Trailing plasma drug concentrations delay both detectable recrudescent primary and secondary blood stage infections—however, both effects are fading until day 42. <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050227#pmed-0050227-g001" target="_blank">Figure 1A</a> illustrates that most recrudescent primary infections are captured by day 42. Extension of follow-up beyond day 28 results in increased ratios of new versus recrudescent infections and hence, elevated risk of outcome misclassifications due to intrinsic limitations of current molecular techniques used to discriminate between primary and secondary infections. The assessment of the total number of recurrent infections as a composite outcome (often denoted the PCR “uncorrected cure rate”) requires some time limits as re-infection occurs eventually in almost everyone after blood concentrations of the drug(s) fall below the MIC (<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050227#pmed-0050227-g001" target="_blank">Figure 1B</a>).</p