An Application of a Physiologically Based Pharmacokinetic Approach to Predict Ceftazidime Pharmacokinetics in a Pregnant Population

Abstract

Physiological changes during pregnancy can alter maternal and fetal drug exposure. The objective of this work was to predict maternal and umbilical ceftazidime pharmacokinetics during pregnancy. Ceftazidime transplacental permeability was predicted from its physicochemical properties and incorporated into the model. Predicted concentrations and parameters from the PBPK model were compared to the observed data. PBPK predicted ceftazidime concentrations in non-pregnant and pregnant subjects of different gestational weeks were within 2-fold of the observations, and the observed concentrations fell within the 5th-95th prediction interval from the PBPK simulations. The calculated transplacental clearance (0.00137 L/h/mL of placenta volume) predicted an average umbilical cord-to-maternal plasma ratio of 0.7 after the first dose, increasing to about 1.0 at a steady state, which also agrees well with clinical observations. The developed maternal PBPK model adequately predicted the observed exposure and kinetics of ceftazidime in the pregnant population. Using a verified population-based PBPK model provides valuable insights into the disposition of drug concentrations in special individuals that are otherwise difficult to study and, in addition, offers the possibility of supplementing sparse samples obtained in vulnerable populations with additional knowledge, informing the dosing adjustment and study design, and improving the efficacy and safety of drugs in target populations.

Keywords: GFR; PBPK model; ceftazidime; feto-placenta; pregnancy; renal.

Figure 1

Ceftazidime pregnancy PBPK model structure.

Figure 2

Plasma concentration profiles after intravenous and intramuscular administration of ceftazidime in non-pregnant subjects. Solid lines = predicted means, Dashed lines = 5th and 95th centiles. Data used for model development are shown in plot (A) (squares [13]; circles [21], and diamonds [22]) after i.v. bolus and in plot (B) i.m. (circles [23]; diamonds [22]) dose. Predictions against observation are shown in plot (C) (triangles [21], squares [23], diamonds [22], and circles [28]), plot (D) (triangles [29], squares [23], diamonds [22], and circles [28]), plot (E) (circles [23] and squares [13]), plot (F) (diamond [22], circle [28], and square [30]), plot (G) [31], plot (H) (circles [32] and squares [33]), plot (I) [34], plot (J) [15], plot (K) [22], and plot (L) (circles [21], triangles [35], squares [29], and diamonds [23]). Observed data are mean values, except for Warns et al., [31], Seiga et al., [32], Kohara et al., [33], and Doko et al., [34] were individual data were available. Error bars represent standard deviations. See Appendix A for trial settings.

Figure 3

Maternal plasma concentration (A–D) and clearance (E) profiles after intravenous (A,B,D) and intramuscular (C) administration of ceftazidime in pregnant subjects at different gestational weeks (plot (A) 7–12 GWs [37]; plot (B): 7–11 GWs (open circles [38] and closed circles [39]), plot (C) [40], plot (D) [41], and plot (E) [42]). Solid lines = predicted means, Dashed lines = 5th and 95th centiles. Error bars in the first plot represent standard deviations. The rest of the observed data are individual values. See the Appendix B for trial settings.

Figure 4

Maternal plasma, umbilical vein plasma, and amniotic concentration profiles after intravenous administration of ceftazidime in pregnant subjects at delivery. Plot (A1,A2) at 25–34 GWs [43], plot (B1–C6) at delivery > 37 GWs (open circles [44], open triangles [41], filled circles [45], diamonds [39], squares [46] closed triangles [38], and crosses [47]. (B1–B6) after single 1 g i.v. dose, and (C1–C6) after a single 2 g i.v. dose. Solid lines = predicted means, Dashed lines= 5th and 95th centiles. Observations are individual values from different studies. See Appendix B for trial settings.

Figure 5

PBPK predictions for maternal and umbilical ceftazidime plasma concentration profiles in pregnant subjects at 20 GWs with 100% (A–D), 75% (E,F), 50% (G,H) of a normal GFR for their gestational week. Solid profiles = predicted means, Dashed profiles = 5th and 95th centiles. Horizontal lines represent MIC of 8 mg/L. inf. = infusion. Plots (A–H) correspond to Cases 1–8, respectively (See Materials and Methods section).

Figure 6

PBPK predictions for maternal and umbilical ceftazidime plasma concentration profiles in pregnant subjects at 30 GWs with 100% (A–D), 75% (E,F), 50% (G,H) of a normal GFR for their gestational week. Solid profiles = predicted means, Dashed profiles = 5th and 95th centiles. Horizontal lines represent MIC of 8 mg/L. inf. = infusion. Plots (A–H) correspond to Cases 1–8, respectively (See Materials and Methods section).

Figure 7

PBPK predictions for maternal and umbilical ceftazidime plasma concentration profiles in pregnant subjects at 40 GWs with 100% (A–D), 75% (E,F), 50% (G,H) of a normal GFR for their gestational week. Solid profiles = predicted means, Dashed profiles = 5th and 95th centiles. Horizontal lines represent MIC of 8 mg/L. inf. = infusion. Plots (A–H) correspond to Cases (1–8), respectively (See Materials and Methods section).