Bottom-up Meets Top-down: Complementary Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling for Regulatory Approval of a Dosing Algorithm of Valganciclovir in Very Young Children.

Population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) models are frequently used to support pediatric drug development. Both methods have strengths and limitations and we used them complementarily to support the regulatory approval of a dosing algorithm for valganciclovir (VGCV) in children <4 months old. An existing pediatric PBPK model was extended to neonates and showed that potential physiological differences compared with older children are minor. The PopPK model was used to simulate ganciclovir (GCV) exposures in children with population typical combinations of body size and renal function and to assess the effectiveness of an alternative dosing algorithm suggested by the US Food and Drug Administration. PBPK and PopPK confirmed that the proposed VGCV dosing algorithm achieves similar GCV exposures in children of all ages and that the alternative dosing algorithm leads to underexposure in a substantial fraction of patients. Our approach raised the confidence in the VGCV dosing algorithm for children <4 months old and supported the regulatory approval.

[Duplex Doppler ultrasonography of intra-renal arteries. Normal and pathological aspects]. / Echo-Doppler pulsé des artères intra-rénales. Aspects normaux et pathologiques.

Duplex Doppler ultrasonography may explore renal perfusion in frequent diseases such as renal obstruction, reno-vascular hypertension, acute or chronic renal failure or diabetic renal complications by measuring Pourcelot's resistive index (RI) of renal parenchyma arteries for each kidney. A statistical and prospective study was performed on 574 patients. In healthy patients, the RI values, equal for each kidney were included in 0.45 and 0.7 (mean RI = 0.59). For other values, there was a renal pathology. Patients with idiopathic hypertension (mean RI = 0.59) or non obstructive dilatation (mean RI = 0.61) did not have an RI significantly different from healthy patients. In cases of renal obstruction, there was a significant increase in the RI for the pathological kidney (mean RI of 0.73). The sensitivity and the specificity was 100% for acute obstructions examined during the first 48 hours. In contrast, in case of renal artery stenosis greater than 70% there was a significant decrease in the RI for pathological kidney. So the RI increased significantly in both kidneys: when there was renal failure with active disease within the tubulo-interstitial compartment (mean RI of 0.77); in all cases of diabetic nephropathy (mean RI of 0.74) where the RI increased early before laboratory signs. Duplex Doppler ultrasonography may be an original method for renal explorations by providing not only morphological data but also physiological data with the perfusion study.