70 kg 60 y male Scr 2 mg/dl. Loading Dose: 160 mg Maintenance Dose: 80 mg q8h

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1 1 Nmgram t NextDse Bdy Size, Maturatin and Organ Functin Presented n the ccasin f being awarded the American Cllege f Clinical Pharmaclgy Distinguished Investigatr award 17 Sep 217, San Dieg, CA, USA. Nick Hlfrd Dept Pharmaclgy & Clinical Pharmaclgy University f Auckland 2 Gentamicin Nmgram 7 kg 6 y male Scr 2 mg/dl Lading Dse: 16 mg Maintenance Dse: 8 mg q8h My first jb as a medical dctr was a Huse Surgen at Macclesfield Hspital in I nly did minr surgery but I wn acclaim frm my surgical clleagues fr predicting dses f gentamicin using Gerge Mawer s nmgram. The nmgram uses weight, age, sex and serum creatinine fr lading and maintenance dses. Dsing was always 8 hurly. I carried paper cpies f the nmgram with my in my pcket and culd quickly recmmend a dse in patients needing gentamicin fr treating surgical infectins. There were n measurements f gentamicin available at that time s there was n questin f further individualizatin. Mawer GE, Ahmad R, Dbbs SM, McGugh JG, Lucas SB, Tth JA. Prescribing aids fr gentamicin. Br J Clin Pharmacl. 1974;1(1): Bdy Size is the mst imprtant quantitative determinant f drug dse The human bdy weight range varies frm abut 5 g t ver 25 kg due t bth bilgical variability and changes ver the lifespan. This mre than 5 fld range in size is directly translatable thrugh vlume f distributin int drug lading dse differences Because f allmetrically predictable relatinships beween weight and clearance the crrespnding range f maintenance dse rates is nly abut 1 fld Shrtly befre I tk up my first medical jb in 1972 I was examined rally fr and wn a prize fr medicine. One f the exam questins was hw t individualize the use f azathiprine (a questin asked by a neurlgist). I figured ut the answer was t use weight and prescribe a mg/kg dse. At the time that was cnsidered highly sphisticated. Tday we can recgnize that weight is the mst imprtant single cvariate fr dse individualisatin in humans. Weight explains at least a 1 fld difference in dse in rder t maintain a target cncentratin.

2 4 Theretical Fundatin fr Allmetric Scaling West GB, Brwn JH, Enquist BJ. The furth dimensin f life: fractal gemetry and allmetric scaling f rganisms. Science. 1999;284(542): The fundamental assumptin f West s allmetric thery is that all cells are similar in size and have similar energy requirements. The structure f the energy delivery system e.g. bld vessels in humans, requires a certain mass e.g. bnes in humans, t supprt the delivery system as well as the target cells. The mass verhead frm these delivery and supprt systems increases ttal bdy mass withut a linear increase in functin. The allmetric expnent value f ¾ describes this nn-linear relatinship fr clearance. This cncept is true fr bth animals (e.g humans r elephants) and plants (e.g. sequia r kauri). In cntrast t functinal prcesses such as clearance, allmetric thery predicts a linear relatinship between mass and structural prperties such as vlume f distributin. The allmetric expnent fr vlume f distributin is 1. Pht shws Nick Hlfrd (41 y 8 kg) and Sam Hlfrd (1 y 8 kg) n Fx Glacier, NZ Renal Functin Renal functin based n GFR are imprtant but still less than weight after accunting fr bdy size. Differences in renal functin can explain abut a 1 fld difference in ttal drug clearance. Glmerular Filtratin Rate» 7 L/h in healthy yung adult».5 L/h in terminal renal failure There is always sme nn-renal clearance e.g. via the gut which adds.5 L/h t renal clearance even in renal failure

3 CL L/h CL L/h CL L/h/kg 6 Hepatic Functin Difficult t predict hepatic drug clearance withut administering the drug Liver Functin Tests» measure liver damage which is nt the same as functin Ppulatin predictins f hepatic functin are pssible but individual predictins d nt have any reliable bimarkers like serum creatinine fr renal functin. MELD=Mdel fr Evaluatin f Liver Disease HPSE=Hepatic Prtal Systemic Elements Clinical Staging Systems» Childs Pugh system/meld/hpse» Lsely crrelated with hepatic drug clearance 7 Maturatin and Ageing Maturatin Of Drug Clearance Typical maturatin is abut 3% f adult values at full term delivery Very premature nenates are arund 1% f adult values In nenates and infants age accunts fr a 1 fld increase in glmerular filtratin rate frm 24 weeks pst-menstrual age up t 1 year f pst-natal age (Rhdin et al. 29). Ageing and Drug Clearance Age in lder adults has a minr (~ 25% lwer) influence n drug clearance nce weight and ther factrs such as renal functin are accunted fr. There is a very imprtant bilgical difference between age in yung humans and ld humans. Yung humans (babies, infants) are immature. They have size apprpriate rgans but have nt yet develped functinal capacity. Old humans lse renal functin as a cnsequence f nephrn lss related t envirnmental hazards (nt age) but d nt lse hepatic functin because the liver regenerates its cells and enzymes irrespective f age. Rhdin, M. M., B. J. Andersn, A. M. Peters, M. G. Culthard, B. Wilkins, M. Cle, E. Chatelut, A. Grubb, G. J. Veal, M. J. Keir and N. H. Hlfrd (29). "Human renal functin maturatin: a quantitative descriptin using weight and pstmenstrual age." Pediatr Nephrl 24(1): Weight and Age Explain Higher mg/kg Dses in Yung Children CL L/h actual CL L/h size CL L/h/kg CL L/h actual Fmat Pst menstrual age weeks Pst natal age years 1% 8% 6% 4% 2% % Clearance increases with weight and age (red line). Allmetric size predicts increasing clearance per kg with lwer weights (green line). Belw 2 years f age immaturity f drug clearance has a majr effect n clearance (see inset) s clearance per kg decreases. This leads t a peak in clearance when expressed per kg arund 2 years f age. Maintenance dses are cmmnly expressed per kg in clinical practice and are als higher arund 2 years f age than in babies and adults. The green line (clearance/kg) is cnsistent with lng standing empirical knwledge f drug dsing in children. It is explained by the cmbinatin f tw bilgical prcesses size and maturatin.

4 9 NextDse NextDse was develped in cllabratin with my sn, Sam Hlfrd (see 4). He created the web interface t the mdelling backend that I wrked n. Bayesian frecaster Published mdels - busulfan - methtrexate - tacrlimus - warfarin - linezlid Simple n the utside Brwser-based web app Clud hsted Sam is nw a practicing medical dctr. We cntinue t wrk n develping NextDse. 1 Technlgy Sftware abstractin layers NONMEM cre - NMTRAN input - Bayesian methdlgy awk pre & pst prcessr - Dse prpsal - Cncentratin predictins PHP + MySQL middleware - User + clinical recrd keeping - Translatin t/frm Awk HTML5 + JavaScript UI 11 A cllabrative effrt Clinicians age weight disease Phlebtmists & nurses bld sample time Pharmacists frmulatin dse time Labratry cncentratin determinatin Cmmn interface fr use at different times and lcatins fr all invlved

5 12 Challenges Mtivatin - Clinical staff - Management Brwser cmpatibility Recrd keeping - Audit trail - Authrisatin Opprtunities Vricnazle Aminglycsides Security - Sftware - Privacy - Lcatin - Reliability Sftware errrs - Catching them - Preventin - Setting expectatins Supprt - Staffing - Back up methds Other medicines Integratin with ther sftware 13 Cnclusin Nmgrams r NextDse?» Interesting intellectual challenges» Scientifically rewarding Clinical pharmaclgy is fun! 14

6 % Adult 15 Rules f PNA and PMA Fractin f adult maintenance dse Typical Weight Kg PMA r PNA Fractin Adult Dse Rule f 'true' % PMA+PNA Adult Errr Dse 1 25 weeks 1/3 1% weeks 1/12 1%.8 3 Full Term 1/3 1% m 1/1 8% m 1/6 24% year 1/5 3% years 1/4-4% years 1/3-11% years 1/2-14% years 3/4-3% Adult 1 1. Weight is cmbined with pst-natal age (PNA) and pst-menstrual age (PMA) t predict the typical dse as a % f the adult dse. The clured areas f the table shw the fractin f adult maintenance dse that wuld be expected fr infants and children. The fractins are based n the theretical size and maturatin mdel fr typical drug clearance with sme apprximatin t make the numbers easier t remember. The rule f PMA+PNA has an acceptable errr fr clinical dse predictin. Althugh maturatin is best described by a nn-linear relatinship it is quite well apprximated by a linear functin f PMA Tramadl TM5 39 weeks Hill 5.8 Dexmedetmidine TM weeks Hill 2.56 Clearance Maturatin GFR TM5 48 weeks Hill 3.38 Paracetaml TM5 52 weeks Hill Cnceptin Full Term Pstmenstrual age (weeks) Mrphine TM5 55 weeks Hill years ld Maturatin is cmplete by 2 years f age then weight is the sle predictive factr fr drug clearance Pst-menstrual age is the recmmended way t describe the bilgical age in weeks after cnceptin. It is based n the mther s recall f the date f the last menstrual perid. It is therefre typically biased by verestimating the age since cnceptin by 2 weeks.