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Paediatric prescribing

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AS Walker1, KL Boyd1, Menson E2, K Butler3, P Tookey4, A Judd1, A Riordan5, D ... very high doses (??salvage) which our model was underpowered to detect ... – PowerPoint PPT presentation

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Title: Paediatric prescribing


1
To overdose or underdose? The question for
Kaletra in children in the UK/Irish CHIPS cohort
AS Walker1, KL Boyd1, Menson E2, K Butler3, P
Tookey4, A Judd1, A Riordan5, D Shingadia6, G
Tudor-Williams7, DM Gibb1 on behalf of the CHIPS
Steering Committee 1 MRC Clinical Trials Unit,
London, UK 2 St Thomass Hospital, London, UK 3
Our Lady's Childrens Hospital Crumlin, Dublin,
Ireland 4 National Study of HIV in Pregnancy
Childhood, Institute of Child Health, London, UK
5 Royal Liverpool Childrens Hospital, Liverpool,
UK 6 Great Ormond St Hospital for Children,
London, UK 7 St Mary's Hospital, London, UK
BACKGROUND how to choose a dose for kids?
Figure 1 Doses received by body surface area
  • For children, the total daily licensed lopinavir
    dose is 460 mg/m2 (600 mg/m2 if used concurrently
    with NNRTI)
  • This was chosen from the first Phase II trial of
    lopinavir in children
  • 100 children were randomised to 460 mg/m2 versus
    600 mg/m2 syrup
  • ART-naive subjects had a 3TCd4T backbone
    ART-experienced patients received NVPNRTI(s)
  • ALL children were escalated to 600 mg/m2 at a
    planned interim review 12-20 weeks after
    randomisation, based on lopinavir
    pharmacokinetics (NOT adjusted for receipt of
    NVP/not)
  • 48 week VL response excellent (79 lt400
    copies/ml) on the higher dose
  • After the trial finished, a post-hoc analysis
    demonstrated the significant interaction between
    NNRTI and lopinavir PK
  • By dose and NNRTI mean AUC Cmin
  • 460 mg/m2, NNRTI 52 1.8 (n14)
  • 460 mg/m2, no NNRTI 73 3.4 (n12)
  • 600 mg/m2, NNRTI 86 3.6 (n12)
  • 600 mg/m2, no NNRTI 116 6.5 (n15)
  • The lower dose (460mg/m2) was therefore licensed,
    even though the VL suppression data were from the
    higher dose (600mg/m2) in all children
  • Some paediatricians therefore prefer to target
    the higher dose, regardless of concomitant therapy

1200
Syrup
Tablet/ Capsule
1000
800
460mg/m2
90-110460mg/m2
600
Absolute daily dose (mg)
400
600 mg/m2
200
90-110600 mg/m2
0
0
.5
1
1.5
2
Body Surface Area (m2)
Table 1 Independent predictors of doses received
Factor (lower dose,higher dose) Independent effect on dose received (mg/m2) 95 CI p
Per year older under 10Per year older over 10 -1-9 -5,3-14,-5 lt0.001
Prior CDC C 17 0,34 0.05
Per unit higher weight-for-age -19 -24,-15 0.001
Per unit higher height-for-age -10 -14,-6 lt0.001
Syrups versus caps/tabs -48 -58,-38 lt0.001
Once versus twice daily -22 -40,-4 0.02
Per log10 higher viral load 2 0,3 0.02
OBJECTIVES
  • In children taking lopinavir WITHOUT NNRTI
  • What doses of lopinavir are paediatricians in
    CHIPS using?
  • What factors affect which dosing scheme is
    followed?
  • Is there any relationship between dose and viral
    load suppression?

High viral load an independent predictor of
higher dose in the 2297 doses with prior VL
available
PREDICTORS OF DOSE RECEIVED
  • The mean dose for a 10 year old, without prior
    CDC C event, average weight- and height-for-age,
    on capsules/tablets twice daily was 546 mg/m2
  • Lower doses in children taking syrups or once
    daily lopinavir likely reflect greater precision
    to target a specific daily dose
  • There was no effect of sex, calendar year, prior
    use of a PI, or most recent prior CD4 on
    current dose
  • Dosing varied widely by centre with some centres
    generallyfollowing lower doses and others
    higher doses (Figure 2)

METHODS
  • CHIPS collects details of all ART doses
    prescribed, as well as height and weight
  • We calculated lopinavir dose in mg/m2 every time
    height/weight was measured, as the fact that
    measurements were made meant that there had been
    an opportunity to change dose. We used CHIPS data
    to December 2007.
  • We excluded doses/measurements when children were
    taking lopinavir with NNRTIs
  • We investigated predictors of current dose in
    mg/m2, including sex and other factors that would
    be known at the current clinic visit
  • VL and CD4 at the previous visit (?14 ?183
    days previously)
  • current age, CDC stage, height/weight-for-age,
    calendar year, formulation (syrup versus
    capsules/tablets), frequency (once versus twice
    daily)
  • previous use of a protease inhibitor
  • using mixed models with random effects for child
    and hospital, and autoregressive errors (based on
    date) for multiple measurements per child.
  • We then considered two models relating dose and
    VL suppression
  • first lopinavir dose and VL suppression 6 months
    after first lopinavir initiation, using logistic
    regression
  • current lopinavir dose (gt6 months after
    initiation) and next VL suppression using
    binomial mixed models

VIRAL LOAD SUPPRESSION after initiation
  • 160 (58) of the 278 children with dose/m2
    estimated on lopinavir without NNRTI had (i) VL
    gt1000 c/ml in the 6 months before initiating
    lopinavir for the first time, and (ii) lopinavir
    dose calculable in the first 3 months of taking
    lopinavir, and (iii) a 6 month VL response
    recorded
  • 28 lt50 c/ml, 68 lt400 c/ml, 73 lt1000 c/ml
  • We found no evidence that initial lopinavir dose
    was associated with improved VL suppression 6
    months after lopinavir initiation (adjusting for
    baseline viral load and age at initiation)
  • lt400 c/ml OR 1.03 per 50 mg/m2 greater (95 CI
    0.86-1.23) p0.73
  • lt50 c/ml OR 0.83 per 50 mg/m2 greater (95 CI
    0.68-1.02) p0.10
  • this effect was predominantly observed with high
    doses over 600 mg/m2 (OR0.96 per 50 mg/m2
    greater below and 0.60 per 50 mg/m2 greater above
    600mg/m2)
  • this may reflect specific reasons for poorer
    response in children prescribed very high doses
    (??salvage) which our model was underpowered to
    detect

RESULTS who takes lopinavir?
  • 333 (25) of 1336 children in CHIPS since January
    2000 had ever taken lopinavir, 22 (2) having
    only taken it with NNRTIs
  • 238 of the 311 children who had taken lopinavir
    without NNRTIs were still on it at last
    follow-up, totalling 654 child-years on lopinavir
    without NNRTIs
  • Median age at lopinavir initiation was 9.0 years
    (IQR 5.1-12.1), at which point 124/311 (40)
    children had a prior AIDS diagnosis
  • 67 (22) started lopinavir in their first
    3/4-drug ART regimen, 37 (12) as a substitution
    in first-line 3/4-drug ART, 129 (41) as
    second-line/salvage, and 78 (25) received
    lopinavir after prior mono/dual NRTI therapy
  • 684 different doses were recorded in 299/311
    children
  • 355 (52) were syrup, 260 (38) capsules and 69
    (10) tablets
  • only 22 (3) taken as once rather than twice
    daily doses
  • In total, dose/m2 could be estimated 2748 times
    in 278 of these 299 children (Figure 1) (the
    others did not have height/weight recorded)
  • few (147, 6) of these doses were gt10 below the
    460mg/m2 target (lt410 mg/m2)
  • few (228, 9) were gt10 above the 600mg/m2 target
    (gt660 mg/m2)
  • most were gt410-lt530mg/m2 (1145, 46) or
    gt530-lt660mg/m2 (958, 39)
  • Two clear patterns of dosing following the
    different dosing schemes can be seen (Figure 1)

VIRAL LOAD SUPPRESSION on lopinavir
  • Looking more generally, there were 1844 viral
    loads where dose in mg/m2 was calculable in the
    preceding 14,183 days
  • We found no strong evidence that dose was
    associated with improved VL suppression,
    adjusting for age at the viral load measurement
    and including hospital and child level random
    effects (no autocorrelation)
  • lt400 c/ml OR 1.10 per 50 mg/m2 greater (95 CI
    0.96-1.25) p0.16
  • lt50 c/ml OR 0.82 per 50 mg/m2 greater (95 CI
    0.73-0.91) plt0.001
  • again, this effect was predominantly observed
    with high doses over 600 mg/m2 (OR0.92 per 50
    mg/m2 below and 0.63 per 50 mg/m2 above 600
    mg/m2, probably for similar reasons to the model
    for initial response
  • A simple multinomial logit model (clustering on
    child) suggested that increasing dose was
    associated with VL 50-lt400 and gt1000 c/ml
  • IRR0.91 per 50 mg/m2 greater (95 CI 0.80-1.04)
    for lt50 vs gt1000 c/ml
  • IRR1.10 per 50 mg/m2 greater (95 CI 0.97-1.26)
    for 50-lt400 vs gt1000 c/ml
  • IRR0.90 per 50 mg/m2 greater (95 CI 0.75-1.08)
    for 400-lt1000 vs gt1000 c/ml

SUMMARY
  • We found no clear evidence that higher doses were
    associated with improved VL suppression overall
  • Higher doses may be associated with poorer viral
    load suppression in children who are prescribed
    them because of concerns about adherence or who
    have a lot of prior ART experience
  • More sophisticated modelling will be required to
    answer the question about dosing and VL
    suppression (or a trial!)
  • Opinion appears to be split as to the most
    appropriate Lopinavir dose in children, with
    older or less stunted/wasted children or those
    without prior AIDS or with lower VLs more likely
    to receive lower doses, as well as those on once
    daily dosing
  • Doses were also higher with capsules/tablets,
    likely reflecting a preference for over- rather
    than under-dosing with solid formulations when
    exact doses cannot be achieved

We thank the staff, families children from all
the hospitals who participate in CHIPS. CHIPS
Steering Committee K Butler, K Doerholt, S
Donaghy, DT Dunn, T Duong, DM Gibb, A Judd, EGH
Lyall, J Masters, E Menson, V Novelli, C Peckham,
A Riordan, M Sharland, D Shingadia, PA Tookey, G
Tudor-Williams, G Wait. MRC Clinical Trials Unit
DT Dunn, T Duong, L Farrelly, DM Gibb, D Johnson,
A Judd, G Wait, AS Walker National Study of HIV
in Pregnancy Childhood, UCL Institute of Child
Health J Masters, C Peckham, PA Tookey. Funding
NSHPC is funded by the Health Protection Agency,
and has also received support from the UK
Department of Health and the Medical Research
Council. CHIPS is funded by the Department of
Health and in the past received additional
support from Bristol-Myers Squibb, Boehringer
Ingelheim, GlaxoSmithKline, Roche, Abbott, and
Gilead. Republic of Ireland Our Lady's
Childrens Hospital Crumlin, Dublin K Butler, A
Walsh. UK Birmingham Heartlands Hospital,
Birmingham Y Heath, J Sills Blackpool Victoria
Hospital, Blackpool N Laycock Bristol Royal
Hospital for Children, Bristol A Finn, A Foot, L
Hutchison Central Middlesex Hospital, London M
Le Provost, A Williams Chase Farm Hospital,
Middlesex Chelsea and Westminster Hospital,
London D Hamadache, EGH Lyall, P Seery Ealing
Hospital, Middlesex V Shah, K Sloper Glasgow
Royal Hospital for Sick Children, Glasgow C
Doherty, R Hague Great Ormond St Hospital for
Children, London M Clapson, S Fasolo, J Flynn,
DM Gibb, N Klein, K Moshal, V Novelli, D
Shingadia Hillingdon Hospital, London Homerton
University Hospital, London D Gurtin John
Radcliffe Hospital, Oxford A Pollard, S Segal
King's College Hospital, London C Ball, S
Hawkins, D Nayagam Leeds General Infirmary,
Leeds P Chetcuti Leicester Royal Infirmary,
Leicester M Green, J Houghton Luton and
Dunstable Hospital, Luton M Connan, M Eisenhut
Mayday University Hospital, Croydon J
Baverstock, J Handforth Milton Keynes General
Hospital, Milton Keynes PK Roy Newcastle
General Hospital, Newcastle J Clarke, K
Doerholt, C Waruiru Newham General Hospital,
London C Donoghue, E Cooper, S Liebeschuetz, S
Wong Ninewells Hospital and Medical School,
Dundee T Lornie North Manchester General
Hospital, Manchester C Murphy, T Tan North
Middlesex Hospital, London J Daniels, EGH Lyall,
B Sampson-Davis Northampton General Hospital,
Northampton F Thompson Northwick Park Hospital,
Middlesex M Le Provost, A Williams Nottingham
City Hospital, Nottingham D Curnock, A Smyth, M
Yanney Queen Elizabeth Hospital, Woolwich W
Faulknall, S Mitchell Royal Belfast Hospital for
Sick Children, Belfast S Christie Royal
Edinburgh Hospital for Sick Children, Edinburgh
J Mok Royal Free Hospital, London S McKenna, V
Van Someren Royal Liverpool Childrens Hospital,
Liverpool C Benson, A Riordan Royal London
Hospital, London B Ramaboea, A Riddell Royal
Preston Hospital, Preston AN Campbell Sheffield
Children's Hospital, Sheffield J Hobbs, F
Shackley St George's Hospital, London R
Chakraborty, S Donaghy, R Fluke, M Sharland, S
Storey, C Wells St Mary's Hospital, London D
Hamadache, C Hanley, EGH Lyall, G Tudor-Williams,
C Walsh, S Walters St Thomas' Hospital, London
R Cross, G Du Mont, E Menson University Hospital
Lewisham, London D Scott, J Stroobant
University Hospital of North Staffordshire, Stoke
On Trent P McMaster University Hospital of
Wales, Cardiff B O' Hare Wexham Park, Slough R
Jones Whipps Cross Hospital, London K Gardiner
Whittington Hospital, London.
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