Einfluss natürlicher Schwankungen bei einer Phase I Studie am Beispiel renaler Parameter. Reinhard Schinzel vasopharm GmbH Würzburg

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1 Einfluss natürlicher Schwankungen bei einer Phase I Studie am Beispiel renaler Parameter Reinhard Schinzel vasopharm GmbH Würzburg

2 VAS203 Phase I First-in-Man Study VAS203 - NOAEL Cynomolgus: 200 mg/kg b.w. - FIM: 6 h infusion of VAS203 in healthy male volunteers - Unexpected finding in man: Kidney target organ Higher Cmax - Lower NOAEL Man: 10 mg/kg b.w.

3 Phase I Renal Repeated Dose - Renale Parameter Creatine Clearance (12h) Serum: - screa (bedside, every 2 h to 4 h) - Cystatin C (every 12 h) Urine: - Proteins: Albumin, α1-microglobulin, ß2-Microglobulin, N-Acetylglucosaminidase - Sediment - Urine volume (12 h Urine)

4 VAS203 Phase I Verlauf screa 3 x 12 h Infusion 3x 12 h Infusion von 5 mg/kg/tag VAS203 (durch Striche gekennzeichnet, t= 0 : Start der ersten Infusion), Schattierung zeigt Tage an.

5 Phase I Verlauf screa Mean Verum vs. Placebo 3x 12 h Infusion von 5 mg/kg/tag VAS203 Mean verum vs Placebo

6 Phase I Cystatin C 1. Infusion 2. Infusion 3. Infusion 3x 12 h Infusion von 5 mg/kg/tag VAS203 (durch Striche gekennzeichnet, t =0: Start der ersten Infusion), Schattierung zeigt Tage an; Rot: Placebo (Subject 14)

7 VAS203 Phase I Renal Sonstige Renale Parameter - Albuminurie: Alle Proben unter Nachweisgrenze - α1-microglobulin: Alle Proben unter Nachweisgrenze - ß2-Microglobulin: Alle Proben im Normalbereich - N-Acetylglucosaminidase: Alle Proben im Normalbereich - Sediment: Alle Proben ohne pathologische Befunde - Urinvolumen: im Normalbereich, aber ausgeprägte Tag/Nacht-Schwankungen

8 Serum creatinine - problems General: - Knowledge about screa in healthy subjects limited! - Measurements over days, months or weeks but not hours - Knowledge about effects on basal levels but not on variation - Some knowledge on effects of exercise - Variation high at low (normal) screa levels Lamb-E British Renal Association 2005

9 Serum creatinine - problems Analytical problems: Non-specificity (ketones, ascorbic acid etc) -> Unlikely Spectral interferences (icterus/lipaemia/haemolysis) -> No No international standardization -> Time course Non-renal influences: gender, ethnicity and age -> No drugs -> Unlikely muscle mass -> Time course nutrition/diet -> Possible! Lamb-E British Renal Association 2005

10 Phase I screa 3 x 12 h Infusion 3x 12 h Infusion von 5 mg/kg/tag VAS203 (durch Striche gekennzeichnet, t= 0 : Start der ersten Infusion), Pfeile zeigen Hauptmahlzeiten, Schattierung zeigt Tage an.

11 Creatinine screa Diet A: 300 g raw beef B: 300 g cooked beef C: 300 g boiled beef D: 300 g Goulash E: 250 g pork stew Jacobsen et al. BMJ hrs

12 Phase I screa Verlauf nach Mahlzeit Phase I Hours after Lunch

13 Creatinine screa Diet Creatine supplementation minimally impacts creatinine concentrations and renal function in young healthy adults. Creatinine concentrations may increase after long periods of creatine supplementation Pline and Smith. The effect of creatine intake on renal function. Ann Pharmacother :

14 screa Tagesverlauf bei Gesunden Serum Creatinine Vergleich screa Verlauf Mittelwert Verum Tag 1 mit Werten von Pasternack und Kuhlbäck (Scand J Clin Lab Invest :1-7)

15 Phase I GFR measured GFR [ml/min] to - 12h, -12 to -0h 0 to 12h 12 to 24h 0 to 12h 12 to 24h 0 to 12h 12 to 24h 24 to 36h 36 to 48h Day - 1 Day - 1 Day 1 Day 1 Day 2 Day 2 Day 3 Day 3 Day 4 Day 4 3x 12 h Infusion von 5 mg/kg/tag VAS203 Rot: Placebo (Subject 14)

16 GFR As the relationship between GFR and creatinine or cystatin C is exponential, this fact will still be a limitation factor for the estimation of GFR in normal range ( > 60 ml/min/1.73 m 2 ) with both creatinine- and cystatin C-based equations

17 Creatinine Comparison egfr and igfr in patients +/- renal disease circle = CKD, square = kidney donors from Poggio et al. JASN 2005

18 The CKD-EPI equation CKD-EPI equation expressed as a single equation: GFR = 141 min(scr/κ, 1)α max(scr/κ, 1) Age [if female] [if black] where SCr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is for females and for males, min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/ κ or 1. Stevens et al. AJKD :486

19 Cystatin C Cystatin C Proband mit ungewöhnlich niedrigen Werten CysC [mg/l] 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0, t [h]

20 Cystatin C The relative effects of fat versus muscle mass on cystatin C and estimates of renal function in healthy young men Chew-Harris et al Ann Clin Chem. in press Cystatin C was highest in the obese group (0.77 mg/l; 95% confidence intervals [CI] ) and creatinine was highest in the muscular group (90.1 mmol/l; 95% CI ). On multivariate analysis, body fat and GFR (p < 0.003) were significant determinants of cystatin C; muscle mass and age affected creatinine significantly (P < 0.02). Creatinine equations showed significant underestimations of GFR for the muscular group. Body fat is a significant determinant of cystatin C while creatinine concentration is highly affected by muscle mass and age. Body composition plays an important role in the interpretation of renal function.

21 Kidney function in healthy subjects Zusammenfassung: - Wissen über screa in Gesunden limitiert - screa wird aber Methode der Wahl bleiben - Andere Parameter wenig charakterisiert - Leichte Meßbarkeit - Standardisierte Messung möglich - Verbesserte GFR Formeln für Gesunde