Table 5.
Review of published p-PBPK models.
| Compound | Route of administration | Clinical observations | Recommended dose adjustment based on PBPK modeling | Software | Reference |
|---|---|---|---|---|---|
| Acetaminophen | IV and oral dosing | Lower acetaminophen concentrations during pregnancy as compared to non-pregnant women | No dose adjustments since there is lack of data on toxicity of the metabolite NAPQI | Open Systems Pharmacology® | (29) |
| Amoxicillin | IV bolus and infusion | Increased renal clearance during pregnancy and postpartum | May need increased dosing No clinical recommendations |
Open Systems Pharmacology® | (30) |
| Betamethasone | IV, IM and oral dosing | Increased clearance during pregnancy | No clinical recommendations | Simcyp® | (31) |
| Buprenorphine | Sublingual | Decreased buprenorphine exposure during pregnancy as compared to postpartum | Increased dose/ more frequent dosing | Simcyp | (32) |
| Caffeine | Oral dosing | Increased maternal and fetal exposure during pregnancy due to reduced CYP1A2 activity | Limit caffeine intake | GastroPlus® | (33) |
| Caffeine, Midazolam, Nifedipine, Metoprolol Ondansetron, Granisetron, Diazepam and Metronidazole | IV and oral dosing | Increase in clearance of CYP2A6, CYP2E1, CYP2D6 and CYP3A4 substrates and decreased clearance of CYP1A2 and CYP2C19 substrates | Likely changes in dosing No clinical recommendations |
Open Systems Pharmacology® | (34) |
| Caffeine, Metoprolol, Midazolam | IV Bolus, Oral dosing | 100% increase, 30% decrease and a 35% decrease in the exposure of caffeine, metoprolol, and midazolam respectively during pregnancy | Decreased dose for caffeine and increased dose for metoprolol and midazolam | Simcyp® | (35) |
| Cefazolin, Cefuroxime, Cefradine | IV and oral dosing | Increased clearance of the three drugs during pregnancy | Increased dose during pregnancy | Open Systems Pharmacology® | (36) |
| Ceftazidime, Cefuroxime, Fluconazole, Aztreonam, Imipenem, Ceftriaxone | IV and Oral dosing | Decrease of in vivo drug exposure (for all 6 drugs) in pregnant women due to increased renal clearance | No dose changes | Simcyp® | (37) |
| Cefuroxime, Cefazoline | IV infusion, IV bolus or infusion | Model accurately predicts changes in renal clearance for both drugs, however inclusion of postpartum data is necessary for fine tuning | No clinical recommendations | GastroPlus® | (38) |
| Darunavir boosted with ritonavir | Oral dosing | Decreased Darunavir exposure during second and third trimester of pregnancy | Increased dose or dosing frequency during pregnancy | Simcyp® | (39) |
| Dolutegravir | Oral dosing | Dose of 50 mg q.d Dolutegravir provides sufficient fetal exposure, resulting in 90% viral inhibition | No dose changes | Berkeley Madonna | (40) |
| Dolutegravir, Raltegravir | Oral dosing | Decreased exposure during pregnancy | No dose changes | Open Systems Pharmacology® | (41) |
| Emtricitabine and Acyclovir | Oral dosing | Lower emtricitabine and acyclovir concentrations during pregnancy with the lowest concentrations during the third trimester | No dose changes | Open Systems Pharmacology® | (42) |
| Emtricitabine, Dolutegravir, Raltegravir | Oral dosing | Neonatal washout kinetics observed for all three drugs | No clinical recommendations | Open Systems Pharmacology® | (43) |
| Indomethacin | Oral dosing | Higher indomethacin clearance during second trimester as compared to non-pregnant women. | Higher dosing requirement during pregnancy | Gastroplus® | (44) |
| Indomethacin | Oral dosing | Decrease in indomethacin exposure by 14, 24, and 32% in the first, second and third trimester respectively, compared to non-pregnant women. | Additional clinical studies warranted to provide optimal dosing recommendations | Simcyp® | (45) |
| Metformin, digoxin, emtricitabine, midazolam | Oral dosing | Decreased exposure during pregnancy due to increased clearance | No clinical recommendations | GastroPlus® | (46) |
| Metformin, Tacrolimus, Oseltamivir | Oral dosing | Increased renal clearance of metformin during pregnancy as compared to postpartum. 20 % decrease in AUC of tacrolimus between 1st and 3rd trimester. AUC of parent drug (oseltamivir) similar but AUC of metabolite (oseltamivir carboxylate) 30% lower during pregnancy. | No clinical recommendations | Simcyp® | (47) |
| Methadone, Glyburide, Phenytoin | Oral dosing | Increased clearance of methadone and glyburide during pregnancy as compared to postpartum | No clinical recommendations | Simcyp® | (48) |
| Midazolam, Nifedipine, Indinavir | Oral dosing | Increased clearance during pregnancy | No clinical recommendations | MATLAB | (49) |
| Midazolam, Theophylline, Zidovudine, Nevirapine, Emtricitabine, Lamivudine, Ondansetron, Diazepam, Metronidazole, Cefuroxime | IV and oral dosing | Increase in fetal exposure with pregnancy age for all drugs | No clinical recommendations | GNU MCSim | (50) |
| Piperaquine | Oral dosing | Pharmacokinetics unchanged as compared to non-pregnant women | No need for dosage adjustment | Simcyp® | (51) |
| Quetiapine | Oral dosing | Decreased concentrations during pregnancy | Dose increase during pregnancy | Simcyp® | (52) |
| Quetiapine, Aripiprazole | Oral and IV dosing | Progressively decreased plasma concentrations throughout pregnancy | Dose for both drugs needs to be increased in the second and third trimesters. | Open Systems Pharmacology® | (53) |
| Tenofovir, emtricitabine, lamivudine | IV and Oral dosing | Increase in renal clearance of drugs during pregnancy | No need for dosage adjustment | Simcyp® | (54) |
| Theophylline, Paroxetine, Clonidine, Dextromethorphan | Oral dosing | Increased concentration of theophylline during third trimester. 100–200% induction of CYP2D6 during third trimester adequately describes the pharmacokinetics of paroxetine, clonidine and dextromethorphan during pregnancy. | No clinical recommendations | Simcyp® | (55) |
| Ziprasidone | Oral dosing | No significant difference in exposure as compared to non-pregnant women | No dose adjustment necessary | Simcyp® | (56) |