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Table 2 Parameter estimates of the final pharmacokinetic-pharmacodynamic model

From: Population pharmacokinetic and pharmacodynamic properties of artesunate in patients with artemisinin sensitive and resistant infections in Southern Myanmar

Parameter Estimates (% RSE) 95% CI %CV BSV (% RSE) 95% CI
Pharmacokinetics
 Artesunate
  F (%) 100 fix 31.2 (29.4) 19.3–50.8
  MTT (h) 1.34 (18.8) 1.04–1.96 85.3 (24.9) 65.7–133.0
  CLARS/F (l/h) 1750 (8.55) 1570–2090 26.8 (44.3) 11.9–39.1
  VARS/F (l) 1300 (12.6) 1110–1660 74.7 (27.3) 57.8–129
  RUV (%) 73.2 (3.95) 69.3–78.7
 Dihydroartemisinin
  CLDHA/F (l/h) 76.7 (6.99) 69.9–87.8 21.3 (30.3) 13.3–88.1
  VDHA/F (l) 102.0 (8.95) 89.5–119.0 31.6 (40.5) 21.3–131.0
  RUV (%) 58.5 (3.34) 56.6–63.4
 Covariate effects
  aPARAMTT (Log10 parasitaemia) 0.115 (8.88) 0.121–0.156
  aPARAmaxF 1.51 (11.9) 1.35–2.02
  aPARA50F (Log10 parasitaemia) 8.32 (3.58) 8.19–9.21
 Pharmacodynamics
  KGROWTH (48 h−1) 10 fix   
  BASEPARA (Log10) 11.0 (0.704) 10.8–11.1 4.4 (19.6) 3.13–5.78
  ke0 (h−1) 0.123 (33.1) 0.0584–0.188  
  aEC50 (nM) 30.4 (34.2) 13.5–46.1  
  aEmaxS (h−1) 0.268 (5.89) 0.242–0.295 b49.0 (22.4) 34.3–70.1
  EmaxR (h−1) 0.155 (6.08) 0.142–0.172 12.2 (45.5) 6.54–35.8
  PMIX, resistant (%) 56.1 (20.9) 39.1–73.8  
  RUV (%) 33.3 (5.91) 30.5–37.1  
  1. Coefficient of variation (%CV) of between subject variability (BSV) was calculated as 100 × (variance-1)1/2. Relative standard errors (% RSE) were calculated as 100 × (standard deviation/mean). The 95% confidence intervals (95% CI) of parameter estimates were obtained with the Sampling Importance Resampling (SIR) approach
  2. ARS artesunate, BASE PARA baseline parasitaemia, CL clearance, DHA dihydroartemisinin, F bioavailability, K GROWTH parasite multiplication per 48 h parasite cycle, MTT mean transit time, PARA MTT estimated linear effect of parasite density on MTT, PARAmax F maximum effect of parasite density on F, PARA50 F parasite density which produces 50% of the maximum covariate response, P MIX, resistant probability of having an artemisinin-resistant infection, V volume of distribution, EC 50 the DHA concentration which produces 50% of maximum parasite killing effect, Emax R maximum parasite killing effect of a resistant parasite population, Emax S maximum parasite killing effect of a sensitive parasite population, k e0 effect compartment rate constant governing the delayed drug effect, RUV unexplained residual variability
  3. aEstimation of these parameters were obtained by applying a frequentist prior approach using a previously published PK/PD model developed on data from Thailand and Cambodia (37)
  4. bBSV (%CV) of EmaxS was calculated based on simulations (10,000 patients) with an estimated variance of 0.430 and the applied transformation presented in Eq. 7