Dose-Banding: Science,

Evidence and Controversies

Chemotherapy dose-standardisation study day,

Bristol, March 2017.

Professor Graham Sewell

Head of School of Health Professions and

Associate Dean (Research)

Plymouth University, UK

gjsewell@plymouth.ac.uk

Prof Graham Sewell

Dose-Banding: Definition

• Not “rounding” or “capping”

• Calculated (BSA) dose fitted to “bands”. Standard dose used for each

band and supplied as single/combination pre-filled infusions/syringes.

• Systematic approach which allows administration of BSA-derived

doses with limited range of standard pre-filled syringes / infusions.

• Needs agreement with stakeholders, careful implementation of

protocols, staff training etc

Plumridge R and Sewell GJ. Am J Health-Syst. Pharm, (2001), 58, 1760-1764

Prof Graham Sewell

Rationale for Dose-Banding (or alternative)

• Increased compounding workload/pressure year on year

• Outpatient clinic chemotherapy waiting times

• Concerns over risk of compounding errors Compounding error:

646 (8.8%) of 7382 infusions >20% variance from Rx dose. Castagne etal, JOPP 17, 191-196 (2010)

• Drug wastage with delayed/cancelled doses

• Inefficiencies of small-scale compounding

• Recognition that “traditional” chemotherapy dosing has limited

scientific basis

Goals of Dose-Banding

• Enables use of defined, standard doses to support:

a) Batch preparation

b) Automated compounding

c) Industry-prepared licensed infusions

• Control of pharmacy & nursing workload

• Minimal treatment delays, patient waiting reduced/eliminated.

• Prospective QC & end-product testing

• Medication and compounding errors reduced/eliminated

• Drug wastage minimised/eliminated

• Can be used in clinical studies (protocol permitting)

Prof Graham Sewell

Controversies in Dose Banding

1. Can pharmaceutical issues be

overcome?

2. Patient issues: Is therapeutic outcome

compromised?

3. Will Prescribing Physicians engage and

support dose-banding?

Controversy (1): Pharmaceutical Issues

• Stability of pre-made infusions for extended shelf-life

• Design of stability studies

• QA and QC of pre- made infusions

• Safe dispensing and administration of pre-made infusions

Prof Graham Sewell

Prof Graham Sewell

Prof Graham Sewell

QC & Prospective End-product Testing

Prof Graham Sewell

End-Product Testing (QC) of Pre-filled

Syringes and Infusions

• Batch preparation (from bulk solution)

• Prospective analysis

- drug assay

- drug identification

• Prospective sterility test

• Prospective microbiological monitoring;

- broth simulations, finger-dab plates, etc

Assurance of Quality, Safety, Efficacy

Prof Graham Sewell

Controversy (2): Patient Issues

• Are we introducing

(another) systematic error

in dosing?

• Is difference between

banded and individualised

dose clinically significant?

• Effect on treatment

outcome and toxicity?

Prof Graham Sewell

How Accurate/Relevant are Traditional

Methods of Cytotoxic Dosing ?

• Only one drug has clear pharmacological basis for dosing (Carboplatin). Others are dosed by BSA.

• Use of BSA arises from interspecies dosing (animals to humans) in Phase 1 studies.

• BSA does not correlate well to drug clearance, plasma or tumour levels.

• Errors in BSA calculation (DuBois and DuBois, Arch. Int.Med 1916 : 17 :863-71)

• No basis for physiological scaling within species

• Purpose of BSA-dosing: Reduce inter-patient variability, not therapeutic optimisation

Prof Graham Sewell

Chemotherapy: Key patient factors

Genetic Polymorphism in Cytotoxic Metabolism

Error and Variation In Conventional

Chemotherapy Dosing

• Measurement of patient Height and Weight

• Error in calculation of BSA – based dose

• Drug potency (+ 5 %)

• Compounding error: 646 (8.8%) of 7382 infusions >20% variance from Rx dose. Castagne etal, JOPP 17, 191-196 (2010)

• Administration;

- spillage

- priming of lines

- syringe accuracy (4 – 5% error)

• Patient-related factors (organ function, lean body mass, enzyme polymorphism etc)

• Oral Chemotherapy: E.g. Capecitabine, 150mg & 500mg tablet

Prof Graham Sewell

In-Vitro Laboratory Simulation of dose-

Banding with Oxaliplatin

• Simulation to compare 5 dose-methods for Oxaliplatin

• 10 simulated “patients” BSA: 1.29 - 2.70m2 (actual pt population)

• Individual dosing (IND) 85mg/m2

• Dose-Banding 5% (max from Rx dose), 12 bands, range 95-230mg

• Dose-Banding 10%, 7 bands, range 95-230mg

• Logarithmic Dose-band, 9 bands, range 84.6-230.9mg

• Flat-fixed Dosing based on population mean BSA (licenced dose x 1.79m2) = 152.15mg

• Scale –down infusion by factor of 40, simulate administration and oxaliplatin clearance, measure “plasma” level and AUC

• Individual and Flat-fixed doses administered as single infusion, banded doses administered as 2-3 standard infusions via manifold

Laboratory Simulation of Dose-banding with Oxaliplatin

Patient BSA

(m2)

Dose in

IND (mg)

5%DB scheme 10%DB scheme FFD scheme LDB scheme

Dose

(mg)

Dose

Difference

(%)

Dose

(mg)

Dose

Difference

(%)

Dose

(mg)

Dose

Difference

(%)

Dose

(mg)

Dose

Difference

(%)

Patient 1 2.70 5.74 5.50 4.18 5.75 0.17 4.00 30.31 5.46 4.88

Patient 2 1.82 3.87 3.75 3.10 4.00 3.36 4.00 3.36 3.91 1.03

Patient 3 1.29 2.74 2.75 0.36 2.50 8.76 4.00 45.99 2.80 2.19

Patient 4 1.55 3.29 3.25 1.22 3.50 6.38 4.00 21.58 3.13 5.17

Patient 5 2.20 4.68 4.75 1.50 4.50 3.85 4.00 14.53 4.88 4.27

Patient 6 1.33 2.83 2.75 2.47 3.00 6.01 4.00 41.34 2.80 1.06

Patient 7 1.99 4.23 4.25 0.47 4.00 5.44 4.00 5.44 4.37 3.31

Patient 8 1.72 3.66 3.75 2.46 3.50 4.37 4.00 9.29 3.50 4.37

Patient 9 2.52 5.36 5.50 2.61 5.75 7.28 4.00 25.37 5.46 1.87

Patient 10 2.04 4.34 4.25 2.07 4.50 3.69 4.00 7.83 4.37 0.69

Oxaliplatin Dose “administered” to each simulated patient with different dose schemes

and % variation in dose from Individual (IND) dosing

10.0

12.0

14.0

16.0

18.0

20.0

22.0

24.0

26.0

28.0

30.0

AU

C (

ug-

hr/

ml)

Dosing Methods

IND 5%DB 10%DB FFD LDB

Distribution of “patient”AUC values (n=10) for

simulations with 5 different dose methods

Lab Simulation of Dose-Banding: What can

we learn?

• Administered dose was, in each case, within expected variation

from Rx dose. E.g. DB5%

• LDB scheme did not reduce inter-patient AUC variability

• Range of AUC’s for DB5%, DB10%, LDB were skewed to lower

values c/f Individual dosing (IND)

• IND and FFD – administered as single infusions, but DB5%,

DB10% and LDB administered as combination of 2-3 infusions.

• -ve displacement of DB AUC values attributed to dead-volume of

manifold and lines. Theoretical under-dosing?

• Effect (as % error) magnified by 40-fold scale down of lab system

• Use Standard doses and admin. methods to avoid systematic error

5-FU PK study on individualised Vs banded

Chemotherapy

Hypothesis: No significant difference in 5-FU available to tissues between individualised and banded doses

Use 5-FU AUC as measure of exposure of tissues to drug

• Prospective, open-label, X-over study on FEC, n=26.

• BSA-dose 5-FU, one course individualised, one banded.

• Matched dosing times (circadian pk of 5FU), blood samples taken over 90 minutes

• Patient consent and Ethics approval obtained.

• Validated LC assay of samples for 5-FU.

• Pk model using Win-Nonlin (non-comp. model)

Investigators: Graham Sewell (Universities of Bath and Plymouth )

Tim Perren (St James Hospital, Leeds)

Valerie Walker (St James Hospital, Leeds)

Sabine Kaestner (University of Bath)

Prof Graham Sewell

Prof Graham Sewell

Effect of Dose-Banding on AUC and

Inter-patient Variability in 5-FU AUC

• Effect on AUC

Mean AUC + sd (n=19) - Individual: 1530+506μg.min/mL

- Banded: 1470+428μg.min/mL

AUCDB – AUCIND = -60μg.min/mL p = 0.29 (N/S)

• Effect on Inter-patient variability

Individual Dosing: CV = 31%, n = 19

Dose-Banded: CV = 22%, n = 19

(Literature: CV = 43% Moores et al, Cancer Chemother Pharmacol 33, 472-476)

Prof Graham Sewell

y = 275.87x + 302.98

R² = 0.0503

0

200

400

600

800

1000

1200

1400

0 0.5 1 1.5 2 2.5

5-F

U C

L (

mL

/min

)

BSA (m2)

5-FU CL versus BSA

Prof Graham Sewell

Conclusion: Dose-Band Study

on 5-FU AUC

• Use of PK measures (AUC) is reasonable surrogate for

clinical effect/toxicity

• Differences in AUC variation between IND and DB arms

(of BSA-dose) not significant

• DB does not increase inter-patient variability

• 5-FU clearance is independent of BSA

Prof Graham Sewell

Retrospective PK Study (France)

• Compare BSA-dosing (current practice), dose-banding, and fixed dose

according to pharmacokinetic (PK) criteria

• Very wide dose-bands selected (+14% variation from Rx dose)

• Used individual values of clearance of six drugs (cisplatin, docetaxel,

paclitaxel, doxorubicin, irinotecan, and topotecan) from 1,206 adult

cancer patients

• AUCs corresponding to each dosing method were compared to a target

value of AUC for each drug:

AUCtarget= standard dose (mg/m²) / mean observed CL (L/h/m²)

Chatelut et al Br J Cancer (2012), 107, 1100-1106

Differences in AUC compared to target AUC

Retrospective DB Study (Chatelut etal):

Conclusion

• Clearance poorly correlated with BSA. BSA-dosing gave better precisions

than fixed dose (cisplatin, docetaxel, paclitaxel, and topotecan).

• Except for paclitaxel, dose-banding did not make precision significantly

worse than that of BSA-dosing. – even with the wide bands (+14%) used in

this study

• Although it was significantly different for paclitaxel, precision of dose-

banding (i.e., 32.0%) was clinically similar to that of BSA-dosing (i.e.,

30.7%). The distribution of the percent error confirms AUC for dose-banding

is similar to BSA-dosing, even for paclitaxel.

Chatelut et al Br J Cancer

Controversy (3): UK Survey of

Physician Opinion on Dose-Banding

• Design based on meetings / focus groups with prescribers

in Kent and Oxford

• Short questionnaire; validated and piloted

• Posted to 1106 oncologists/haematologists identified in

2006 Directory of Cancer Care

Prof Graham Sewell

Summary of responses to questions 1 – 7 of questionnaire.

Question Yes No Don’t

Know

No

Response

1. Do you have concerns about the time

out-patients have to wait?

281 (74%) 93 (25 %) 5 (1%) -

2. Have you heard about dose-banding

previously?

308 (81%) 71 (19%) - -

3. Does your hospital use dose-banding? 238 (63%) 83 (22%) 20 (5%) 37 (10%)

4. Do you think dose-banding is sensible? 308 (81%) 10 (3%)

55 (15%) 6 (2%)

5. Do you think there are benefits with

dose-banding?

349 (92%) 4 (1%) 7 (2%) 19 (5%)

6. Which do you think

the maximum

deviation from the

individualised dose

should be?

< 5% 197 (52%) 7 (2%)

< 10% 150 (40%)

< 15% 8 (2%)

Other/do not

know

17 (4%)

7. Would it be

acceptable to dose-

band drugs with non

BSA-based dose?

a. carboplatin 203 (54%) 79 (21%) 70 (18%) 27 (7%)

b. targeted

antibodies

232 (61%) 37 (10%) 72 (19%) 37 (10%)

Prof Graham Sewell

Opinions on acceptable maximum deviation from exact BSA-based dose according to occupation

C; clinical oncologist, M; medical oncologist, H; haematologist, P; paediatrician oncologist; O; other, ND; not defined.

Prof Graham Sewell

Comments opposed to dose-banding of carboplatin: “almost certainly not” “GFR [renal function] measurement can vary” “dosing depends on GFR each cycle” “would need looking at potential inaccuracies/problems” “not sure of evidence either way” Comments in support of dose-banding carboplatin: “provided that it is within 5% of the estimated dose” “provided that the patient is not old and has co-morbidities or poor renal function” “yes, as creatinine clearance also has a wide error band” “yes, providing dose is calculated with [Calvert] formula”

Carboplatin Dose-banding: Qualitative responses

Prof Graham Sewell

UK Survey: Summary

• Oncologists mainly supportive of Dose-banding

• Mixed views on max variance from Rx dose (5% Vs 10% Vs 15%)

• Some concerns about Carboplatin and targeted therapies

• Lack of evidence/published studies highlighted

Prof Graham Sewell

Dose-Banding: Summary

• Scientific rationale

• Increasing Pharmaceutical and Clinical evidence/experience.

• UK Prescriber support for dose-banding

• Approved for many UK clinical trials

• 15 years clinical experience – widely adopted

• Clear benefits + Improved patient care, safety and quality

• Need harmonisation of schemes to encourage RTU products from industry. Need further research on DB schemes, administration systems and max. variation from Rx dose

Acknowledgements: Sabine Kaestner, Tim Perrin,

Nicola Stoner, Jing Xu, Richard Plumridge, Val Walker, Toral Patel

Dennis Yianakis, Xiaoqing Liu, Asha Kattige, Milena Massimini

Prof Graham Sewell

Bibliography

• Plumridge R, Sewell GJ: Dose-banding of cytotoxic drugs; a new concept in cancer chemotherapy. Am J Health-Syst. Pharm. 2001, 58, 1760-1764

• Kaestner S, Walker V, Perren T, Sewell GJ: Clinical and pharmacokinetic study on dose-banded and individual chemotherapy. J Oncol Pharm Pract. 2004, 10, 100

• Kaestner S, Walker V, Perren T, Sewell GJ: Pharmacokinetic assessment of dose-banded chemotherapy. Pharmacotherapy, 2005, 25, 1545

• Kaestner S and Sewell GJ: Pharmacoeconomic aspects of dose-banding. Hospital Pharmacy Europe., 2006, 26, 33-34

• Kaestner S and Sewell GJ. Chemotherapy Dosing Part 1: Scientific basis for current practice and use of BSA. Clinical Oncology (2007), 19, 23-37

• Kaestner S and Sewell GJ, A sequential temperature cycling study for investigation of carboplatin infusion stability to facilitate dose-banding. J Oncol Pharm Pract (2007), 13(2), 119-126

Prof Graham Sewell

Bibliography continued……..

• Kaestner S and Sewell GJ. Chemotherapy Dosing Part II: Alternative approaches and future prospects. Clinical Oncology (2007), 19, 99-107

• Kaestner S and Sewell GJ. Dose-banding of carboplatin: Rationale and proposed banding scheme. J Oncol Pharm Pract (2007), 13, 109-117

• Kaestner S and Sewell GJ. Survey of UK Prescribers on Chemotherapy Dosing and Dose-banding. Clinical Oncology (2009), 21, 320-328

• Bardin, C., Astier, A., Sewell GJ, Vulto, A., Vigneron, J., Trittler, R., Pinguet, F. (2011). Guidelines for the pratical stability studies of anticancer drugs: A European consensus conference. Annales Pharmaceutiques Françaises 69(4), 221-231

• Kaestner S and Sewell GJ. Chemotherapy dose-adaption according to organ function and pharmacokinetics. Hospital Pharmacy Europe (2010) 52, 55-57

Prof Graham Sewell