Cancer Chcmotlicr Pharmacol (1982) 10:33-35
`
`Fjancer
`C hemotherapy and
`Lllharmacology
`© Springer—Verlag 1980
`
`Tamoxifen (Nolvadex*) Therapy — Radionale for Loading Dose
`Followed by Maintenance Dose for Patients
`with Metastatic Breast Cancer
`
`P. M. Wilkinson‘, G. G. Ribiero‘, H. K. Adamz, J. V. Kemp’, and J. S. Pattersonz
`
`‘Christie Hospital and I-Iolt Radium Institute, Manchester M20 9BX,l
`2 Imperial Chemical Industries PLC, Pharmaceutical Division,
`Alderley Park, Macclestield SKIO 4TG, Cheshire, Great Britain
`
`Summary. A loading dose of tamoxifen 100 mg/m2 on day I,
`followed by a maintenance dose of 20 mg daily, achieved mean
`parent drug concentrations ofgreater than 150 ng/ml in 12 of 12
`patients with metastatic breast cancer. This drug concentration
`was achieved on dayl and maintained throughout the study
`period (28 days). This rapid achievement of steady—state serum
`concentrations may be of therapeutic benefit in the management
`of patients with tamoxtfewsensitive tumours.
`
`Introduction
`
`The anti-oestrogenic drug tamoxifen (T) is now used exten-
`sively in the management of metastatic breast cancer. The
`conventional method of administration is to give 20-40 mg
`daily in divided doses, which in the majority of sensitive
`patients does not give a clinical response in less than 6 weeks.
`We have previously demonstrated that with a dose of 10 mg
`b.d., steady-state serum concentrations were not achieved in
`3 weeks and that this observation may be relevant to the delay
`in initiation of response [10]. It was suggested that a loading
`dose followed by a maintenance dose could overcome this
`delay in reaching steady state and might induce more rapid
`clinical response. We now report a pilot study to test this
`hypothesis.
`
`Patients, Materials and Methods
`
`Patients. Fifteen patients with metastatic breast cancer were
`selected for treatment after the study had been explained in
`detail and informed consent obtained. Patients’ liver function
`
`was considered to be normal where the liver was not palpable
`clinically and where serum albumin, bilirubin, and liver
`enzymes were within normal
`limits. All patients treated
`fulfilled these criteria; it was not considered appropriate to
`undertake more detailed assessment of hepatic function.
`Similarly, renal function was considered to be normal in each
`patient in whom the serum creatinine was within the normal
`range for the patient’s age, and all patients had normal renal
`function according to this criterion.
`Three loading dose regimens were selected and adminis-
`tered to three separate patients in a pilot study. The loading
`dose for regimens 1, 2, and 3 was fractionated over 24 h in
`multiples of 40mg. Thus 160 mg was administered as four
`10-mg tablets 4-hourly X 4.
`
`Regimen I
`100 mg day 1; 80 mg day 2; 60 mg days 3, 4; 40 mg days 5,6, 7;
`and 20 mg daily thereafter.
`
`Regimen 2
`160 mg day 1; 20 mg daily thereafter.
`
`Regimen 3
`100 mg day 1, 20 mg daily thereafter.
`
`Blood samples, obtained on days 0, 1, 2, 7, 14, and 28,
`were collected in plain tubes and allowed to clot at room
`temperature. Serum was obtained by centrifugation and stored
`at —20° C prior to assay. Further samples were obtained on
`day 76 (regimen 1) and on day 47 (regimen 3). T and N—des-
`methyltamoxifen (DMT) concentrations were determined by
`the method of Adam et al. [2, 3].
`In terms of simplicity and practicality in achieving the
`desired objective, regimen 2 appeared the most appropriate
`and therefore a further 12 patients were studied in the above
`manner.
`
`Results
`
`Figure 1 illustrates the serum concentrations of T and DMT on
`the three regimens in the pilot study.
`
`Regimen I
`
`A peak T concentration of 300 ng/ml was achieved by day 2,
`followed by a gradual decline to 172 ng/ml at day 28. The peak
`concentration of DMT was not reached until day 14 and
`thereafter exceeded that of parent drug. Taking the day 76
`result as final steady state in this patient, it can be seen that
`with this regimen the T values were always in excess of the final
`steady state but that the metabolite levels took 14 days to
`achieve/exceed the final value.
`
`Regimen 2
`
`Serum concentrations of T remained fairly constant from
`days 1 to 28, with the exception of a small fall on day 2. Peak
`concentrations of DMT were achieved by day 14 and were in
`excess of those of the parent drug.
`
`Regimen 3
`
`Reprint requests should be addressed to P. M. Wilkinson
`" Nolvadex is a trade mark, property of Imperial Chemical
`Industries PLC
`
`If the day 47 result was taken as final steady state in this patient
`the T concentration only achieved this value by day 28 and the
`metabolite levels did not achieve steady state by day 28.
`
`0344-5704/82/0010/0033/ll 01.00
`
`|nnoPharma Exhibit 10860001
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`34
`
`Serumlevel
`
`
`tnglmli
`
`
`5
`
`25
`20
`15
`10
`Time on treatment (days I
`
`30
`
`Fig. 1. Serum concentrations of tamoxifen (O) and N-desmethylta-
`moxifen (O) achieved by three loading dose regimens: 1, 100 mg on
`day 1, 80 mg on day 2, 60 mg on days 3 and 4, 40 mg on days 5, 6, and
`7. and 20 mg daily thereafter; 2, 160 mg on dayl and 20 mgdaily
`thereafter; and 3, 100 mg on dayl and 20 mg daily thereafter
`
`300
`
`200
`
`l3
`.\
`
`100
`
`—,<'.=
`
`U!o
`
`
`
`Serumconcentrationng/mi
`
`0
`
`7
`
`14
`Time on treament (days)
`
`21
`
`28 .
`
`Fig. 2. Mean serum concentrations (mean i SEM) of tamoxifen (O)
`and N-desmethyltamoxifen (O) in 12 patients treated with a loading
`dose of 160 mg followed by a maintenance dose of 20 mg daily
`
`The mean concentrations of T and DMT achieved in the
`
`additional 12 patients studied on regimen 2 are shown in Fig. 2.
`Steady-state concentrations of T were achieved by day 2; the
`concentration of DMT gradually increased to achieve a steady
`state on day 14 and thereafter remained in excess of the parent
`drug concentration. No adverse effects were noted in any of
`the patients treated.
`
`Discussion
`
`The concept of a loading dose followed by a maintenance dose
`is a principle commonly applied to a situation where it
`is
`necessary to achieve an effective therapeutic concentration
`rapidly. What bedevils cancer therapy is the lack of informa-
`tion concerning what
`is an effective concentration of the
`therapeutic agent.
`Tamoxifen is no exception, in that attempts to correlate
`serum concentrations with effect have failed to show a clear
`
`relationship between these parameters. One group failed to
`find any relationship [7], while another has stated that a
`concentration of greater than 150 ng/ml
`is consistent with
`response [4], although in the original study by these workers it
`was shown that levels in responders were not significantly
`different from those in non-responders [5].
`With conventional T therapy, steady-state concentration
`for parent drug and metabolite were not achieved until after 4
`and 8 weeks,
`respectively [2], whilst other workers have
`claimed that periods of up to 16 weeks are required to achieve
`a steady state [5]. Time to clinical response is generally
`accepted as being at least 6 weeks, and median values of 5, 3, 6,
`or 9 weeks have been reported [6-8]. Thus a loading dose
`regimen with T that would allow concentrations of parent drug
`in excess of 150 ng/ml to be reached within 48 h of commencing
`therapy could be a useful approach.
`No information is available concerning relevant concen-
`trations of DMT, but
`it should be recognised that
`this
`metabolite may contribute to the therapeutic effect in man as
`there is evidence of anti-oestrogenic activity in animals equal
`to that of parent drug [9].
`Conceptually it can be argued that a loading dose should
`be more beneficial providing it is free from toxic effects and
`patient compliance is
`satisfactory. Although regimen 1
`achieved the highest initial serum concentration it is probably
`too complicated for satisfactory patient compliance. Regi-
`men 3 failed to yield adequate serum concentrations. With
`regimen 2, i.e., a loading dose of 100 mg/m2 on day 1 followed
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`by a maintenance dose of 20 mg daily, peak concentrations of
`T greater than 150 ng/ml were achieved in all patients by day 1,
`and this was maintained throughout
`the study period.
`Concentrations of DMT achieved a steady-state level by day 14
`and were in excess of those of T for the remainder of the study
`period. It would be more difficult to devise‘ a regimen that
`could achieve steady-state concentrations of DMT quickly, as
`factors governing the metabolism of drugs are complex and the
`‘close regimen selected would almost certainly have to be varied
`because of the heterogeneous nature of patient groups.
`The results in this study can be contrasted with those of
`Fabian et al.
`[10], who observed that a loading dose of
`40 mg/m2 b.i.d. daily for 7 days yielded serum concentrations
`> 200 mg/ml within 3days. Concentrations considerably in
`excess of these were attained from day 4 onwards even with a
`maintenance dose of 20 mg/m2 daily. On present evidence of T
`kinetics a b.d.
`loading schedule over 7days is somewhat
`excessive and daily administration would probably be suffi-
`cient. The selection of the loading dose in this study was
`derived from our previous study. For practical purposes it was
`felt
`that
`the most simplistic regimen suitable for patient
`compliance should be selected and we suggest that regimen 2,
`with approximately 100 mg/ml on day 1, is adequate to achieve
`serum concentrations currently believed to be satisfactory, and
`that this schedule could be used in the context of a clinical
`trial.
`
`References
`
`1. Adam HK, Gay MA, Moore RH (1980a) Measurement of
`tamoxifen in serum by thin-layer densitometry. J Endocrinol
`84:35-41
`
`35
`
`2. Adam HK, Patterson IS, Kemp JV (19801)) Studies on the
`metabolism and pharmacokinetics of tamoxifen in normal volun~
`teers. Cancer Treat Rep 64: 761-764
`3. Fabian C, Sternson L, Bennett M (1980) Clinical pharmacology of
`tamoxifen in patients with breast cancer: comparison of traditional
`and loading dose schedules. Cancer Treat Rep 64: 765-773
`4. Fabian C, Tilzer L, Sternson L (1981a) Comparative binding
`affinities of tamoxifen, 4—hydroxytamoxifen and desmethyltamox—
`ifen for estrogen receptors isolated from human breast carcinoma:
`correlation with blood levels in patients with metastatic breast
`cancer. Biopharmacology and Drug Disposition 2: 381-390
`5. Fabian C, Sternson L, El-Serafi M, Cain L, Hearne G (1981b)
`Clinical pharmacology of tamoxifen in patients with breast cancer.
`Correlation with clinical data. Cancer 48: 876-882
`6. Nagai R, Kumaoka S (1980) Clinical evaluation of tamoxifen in
`advanced breast cancer (primary and recurrent) - double blind
`study. Clinical Evaluation 8: 321-352
`7. Patterson J S, Settatree RS, Adam HK, Kemp JV (19890) Serum
`concentrations of
`tamoxifen and major metabolite during
`long-term Nolvadex therapy, correlated with chemical response.
`In: Mourisden H, Palshof T (eds) Breast cancer: experimental and
`clinical aspects. Pergamon, London, pp 89-92
`8. Tormey DC, Simon RM, Lippman RB, et al (1976) Evaluation of
`tamoxifen dose in advanced breast cancer; a progress report.
`Cancer Treat Rep 60: 1451-1459
`9. Wakeling AE, Slater SR (1979) Oestrogen receptor binding and
`biological activity of tamoxifen and its metabolites. Cancer Treat
`Rep 64: 741-745
`_
`10. Wilkinson PM, Ribeiro GG, Adam H, Patterson J (1980) Clinical
`pharmacology of tamoxifen and N-desmethyltamoxifen in patients
`with advanced breast cancer. Cancer Chemother Pharmacol
`5: 109-111
`
`Received May 12/Accepted September 27, 1982
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