Table 1.
Overview on the pharmacokinetics (PK) of drugs in neonates undergoing therapeutic hypothermia (TH), obtained by a structured Pubmed search.
| PMID | Drug | Log P | Study related aspects and findings |
|---|---|---|---|
| 30300445 | gentamicin | −3.1 | N = 12 WBH neonates, 2.2, SD 0.7 ml/min/kg |
| 29781085 | gentamicin | −3.1 | pooled data, 8 studies in WBH and non-WBH neonates, trough (+35%) higher, clearance (−31%) lower in WBH neonates. |
| 26763684 | gentamicin | −3.1 | N = 47 WBH neonates during and after cooling, +29% clearance after cooling. |
| 25225917 | gentamicin | −3.1 | N = 41 WBH neonates, external validation of the PIMD 23553582 dosing regimen. |
| 25070069 | gentamicin | −3.1 | N = 15 WBH vs 19 non-WBH asphyxia neonates, elimination half-life 9.57 vs 7.01 h, +36%. |
| 23702622 | gentamicin | −3.1 | N = 29 + 23 WBH neonates, 5 mg/kg.q24 h to 36 h dosing strategy, elevated trough (>2 mg/l) 38 to 4%. |
| 23553582 | gentamicin | −3.1 | N = 29 WBH neonates, clearance 0.111 × (weight/3.3 kg)0.75 × (1/crea, mg.dl)0.566. |
| 23503448 | gentamicin | −3.1 | N = 16 WBH neonates vs 7 non-cooled asphyxia neonates, clearance -25 %, elimination half-life +40 %. |
| 28993332 | amikacin | −7.4 | N = 56 WBH neonates, compared to noncooled, nonasphyxia cases, clearance −40.6%. |
| 28226400 | ampicillin | 1.35 | N = 13 WBH neonates, clearance lower (−66%), volume of distribution higher (+30%) compared to historical data. |
| 28555724 | amoxicillin | 0.87 | N = 125 WBH neonates, during and after cooling, clearance increases after cooling (0.26 to 0.41 l/h, +58%). |
| 29378710 | benzyl-penicillin | 1.83 | N = 41 WBH neonates, clearance 5.33 l/h.70 kg (system information from PIMD 28555724). |
| 29357720 | phenobarbital | 1.47 | N = 26 WBH neonates, clearance is lower (−15%), because disease severity in WBH neonates affects clearance (−55%). |
| 23254984 | phenobarbital | 1.47 | N = 39 asphyxia neonates, 20/39 underwent WBH, hypothermia was not a significant covariate for clearance. |
| 23018530 | phenobarbital | 1.47 | N = 31 WBH neonates, typical newborn (3.5 kg) 17.2 ml/h, weight as covariate (kg0.81). |
| 21371018 | phenobarbital | 1.47 | N = 19 WBH neonates, half-life 173.9, SD 62.5 h |
| 19744111 | topiramate | −0.7 | N = 13 WBH neonates, (oral), half-life 35.58, SD 19.3 h (deep vs mild hypothermia, 30–33 vs 33–34°C, half-life + 38%) |
| 31336401 | topiramate | −0.7 | N = 52 WBH neonates, (oral), PK during and after cooling (clearance +21% after cooling) |
| 28099423 | erythropoetin | n.a. | N = 47 WBH neonates, pooled from previous studies, clearance 0.0289 l/h, weight0.75 covariate (1.27) |
| 23008465 | erythropoetin | n.a. | N = 24 WBH neonates, nonlinear pharmacokinetics (half-life 7.2–18.7 h, clearance 15.6–7.7 ml/h.kg) |
| 25989868 | darbepoetin alfa | n.a. | N = 16 WBH neonates exposed, clearance 0.0465 l/h |
| 25996892 | darbepoetin alfa | n.a. | N = 30 WBH neonates, different doses (placebo, 2 or 10 µg/kg <12 h and 7 days), linear pharmacokinetics |
| 24288267 | midazolam | 4.33 | N = 9 WBH neonates, half-life 13 (2.75–50.52) h; clearance: 2.57 ml/kg/min, renal or hepatic impairment affects clearance |
| 31256150 | midazolam+phenobarbital | 4.33/1.47 | 68 WBH neonates, phenobarbital coexposure increases midazolam clearance (factor 2.3) during cooling |
| 30734962 | melatonin | n.a. | N = 5 WBH neonates, (oral), 0.21, SD 0.07 l/h. |
| 26189501 | bumetanide | 2.6 | N = 13 WBH neonates, 1 noncooled, mean clearance 0.063 l/h, weight1.7 as covariate |
| 23303304 | lidocaine | 2.44 | N = 22 WBH neonates, compared to N = 26 historical noncooled asphyxia neonates, clearance −24% |
| 18381513 | morphine | 0.89 | N = 10 WBH neonates, and N = 6 non-cooled asphyxia neonates, clearance 0.69 vs 0.89 ml/min.kg (−22%) |
| 27225747 | morphine | 0.89 | N = 20 WBH neonates, 0.765 vs 1.42–1.53 l/h in non-asphyxia, noncooled historical neonates (−40 and −50% respectively) |
Some of these PK estimates were compared with either noncooling asphyxia cases, nonasphyxia term cases or were compared to PK estimates (paired) after the hypothermia episode. The PMID number, the drug involved, its Log P value (PubChem), study related aspects and key findings have been listed. We refer the interested reader to the original publications (by PMID number) for further details. N, number; PK, pharmacokinetics; SD, standard deviation; WBH, whole body hypothermia.