Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials

Figures & data

Figure 1 Included patients.

Notes: Patients included in the analysis. Study 1 = clinical Phase 1 study with once-weekly once-daily treatment with oral docetaxel (drinking solution, capsules (ModraDoc001, ModraDoc003, ModraDoc004) and tablets (ModraDoc006) co-administrated with ritonavir.³⁴ Study 2 = clinical phase 1 study with once-weekly bi-daily treatment with oral docetaxel capsules (ModraDoc001) and tablets (ModraDoc006) co-administrated with ritonavir.³⁵

Note: The number N represents the number of patients.

Abbreviations: IV, intravenous; PK, pharmacokinetics.

Table 1 Characteristics of the Patients Evaluable for Toxicity

	All Patients (N=138)	Patients without Severe Toxicity (N=104)	Patients with Severe Toxicity (N=34)
Age Mean (range) in years	60 (36–79)	59 (37–79)	61 (36–77)
Gender Male Female	58% (N=80) 42% (N=58)	62% (N= 64) 38% (N=40)	47% (N=16) 53% (N=18)
BSA Mean (range) in m^2	1.95 (1.50–2.42) (N=137)	1.96 (1.54–2.42) (N=104)	1.92 (1.54–2.38) (N=33)
WHO PS 0–1 ≥2	96% (N=132) 4% (N=6)	96% (N=100) 4% (N=4)	94% N=32) 6% (N=2)
Tumor type (frequency >5%) NSCLC Urothelial cell ca Ovarian ca Oesophageal/gastric ca Anal ca	43% (N=60) 12% (N=17) 7% (N=10) 7% (N=10) 5% (N=7)	39% (N=41) 14% (N=15) 9% (N=9) 8% (N=8) 5% (N=5)	56% (N=19) 6% (N=2) 3% (N=1) 6% (N=2) 6% (N=2)
Sites of metastasis Lung/pleural Liver Abdominal/peritoneal Bone Cerebral/leptomeningeal	58% (N=80) 20% (N=27) 17% (N=23) 18% (N=25) 7% (N=10)	58% (N=60) 16% (N=17) 20% (N=21) 21% (N=22) 7% (N=7)	59% (N=20) 29% (N=10) 6% (N=2) 9% (N=3) 9% (N=3)
Prior treatments Systemic therapy lines (number) Palliative (median (range)) Total (median (range)) Gastrointestinal surgery Upper GI-tract (% yes) Lower GI-tract (% yes) Radiotherapy with GI-tract in field Upper GI-tract (% yes) Lower GI-tract (% yes)	1 (0–8) 2 (0–9) 2% (N=3) 9% (N=12) 11% (N=15) 12% (N=16)	1 (0–8) 2 (0–9) 2% (N=2) 10% (N=10) 12% (N=12) 10% (N=10)	1 (0–7) 1 (0–7) 3% (N=1) 6% (N=2) 8% (N=3) 18% (N=6)
Ethnicity Caucasian Black Other	97% (N=134) 1% (N=2) 1% (N=2)	96% (N=100) 2% (N=2) 2% (N=2)	100% (N=34)

Abbreviations: ca, carcinoma; WHO PS, World Health Organization Performance Score; NSCLC, non-small cell lung cancer; GI-tract, gastrointestinal tract; N, number of patients.

Figure 2 Duration of treatment.

Notes: Duration of continuous weekly treatment with oral docetaxel and ritonavir for 138 patients treated in the two phase I trials. Each row represents one single patient. The color indicates the reason for discontinuation, ie disease progression (blue), disease-related complications (grey), treatment-related toxicity (red) or other reasons (white) such as a switch of the oral docetaxel formulation.

Table 2 Severe Toxicities Related to Oral Docetaxel Co-Administrated with Ritonavir

Severe Toxicities^a	Grade	% of Patients	Number of Cycles^c (Median (Range))
Mucositis (stomatitis, oesophagitis, gastritis, duodenitis)	3	7% (N=9)	3 (1–11)	Acute
Fatigue	3	7% (N=9)	4 (1–13)
Diarrhea	3	4% (N=6)	2 (1–4)
Vomiting	2 3	1% (N=1) 4% (N=6)	7 2 (2–4)
Nausea	2 3	1% (N=1) 4% (N=6)	11 2 (2–4)
ASAT/ALAT increase	3	3% (N=4)	2 (1–2)
Febrile neutropenia	3 4	2% (N=3) 1% (N=1)	3 (2–3) 1
Neutropenia	2 4	1% (N=1) 1% (N=2)	2 2 (1–2)
Thrombocytopenia	2 3	1% (N=1) 1% (N=1)	5 2
Anorexia	3	2% (N=3)	2 (1–6)
Chylothorax/chylous ascites	3	1% (N=2)	20 (14–25)	Late
Peripheral fluid retention	3	1% (N=1)	14
Pneumonitis	5	1% (N=1)	11
Skin toxicity^b	3	1% (N=1)	11

Notes: ^aCTCAE ≥grade 3 toxicities that were considered (possibly, probably or definitely) related to the study medication or related toxicities of any grade that have led to discontinuation or a dose reduction of the study medication; ^bCombination of hand–foot syndrome, nail loss, ulcerations on the extremities, diagnosed as either toxicodermia or erythema exsudativum multiforme after skin biopsy analysis; ^cIntended as number of cycles administered before the development of severe toxicity.

Abbreviations: ASAT, aspartate aminotransferase; ALAT, alanine aminotransferase; N, number of patients.

Figure 3 Correlation of the C_max and the AUC of docetaxel.

Notes: The relation between the maximum plasma concentration (C_max) and the area under the plasma concentration versus time curve from zero to infinity (AUC_0-inf) of docetaxel for 138 patients treated with oral docetaxel plus ritonavir. For both parameters, the mean results of cycles 1 and 2 of every individual patient were used. The C_max and AUC_0-inf of docetaxel seem correlated, as assessed with the non-parametric Spearman correlation test (r = 0.85).

Figure 4 Relation of the exposure to ritonavir versus docetaxel.

Notes: The relation between the AUC of ritonavir versus that of docetaxel for 138 patients treated with oral docetaxel plus ritonavir. For both parameters, the mean results of cycles 1 and 2 of every individual patient were used. The AUC of docetaxel and ritonavir seem correlated, as assessed with the non-parametric Spearman correlation test (r = 0.72).

Figure 5 Pharmacokinetic exposure to docetaxel in patients with and without severe toxicity.

Notes: Weekly AUC_0-inf (mean of the first two weekly treatment cycles) on the left Y-axis and C_max of docetaxel on the right Y-axis, in patients without (green boxplots, N=104) and with severe toxicity (red boxplots, N=34). The boxplots show the median AUC_0-inf of 1905 (25% percentile 1233 and 75% percentile 3029) for the severe toxicity group (red) and median AUC_0-inf of 742 (25% percentile 474 and 75% percentile 1247) ng/mL*h of the group without severe toxicity (green) on the left Y-axis. On the right Y-axis, the median C_max of 156 (25% percentile 103 and 75% percentile 209) for the severe toxicity group, as compared to the group without severe toxicity with a median C_max of 110 (25% percentile 59 and 75% percentile 160) ng/mL. Severe toxicity was defined as all CTCAE grade 3 toxicities and/or toxicities of any grade leading to treatment interruption, discontinuation or dose reduction, that were possibly, probably or definitely related to the study treatment. For both PK parameters, the mean was significantly higher (p<0.0001 with two-sided t-test, α=0.05) in the severe toxicity group (mean AUC_0-inf 2231 ± standard deviation (SD) 1405 ng/mL*h and mean C_max 218 ± 178 ng/mL) as compared to the group without severe toxicity (mean AUC_0-inf 1011 ± 830 ng/mL*h and mean C_max 119 ± 77 ng/mL).

De Weger VA, Stuurman FE, Koolen SLW, et al. A phase I dose escalation study of once weekly oral administration of docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir. Clin Cancer Res. 2019;25(18):5466–5474. doi:10.1158/1078-0432.CCR-17-229931217201

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De Weger VA, Stuurman FE, Hendrikx JJMA, et al. A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir. Eur J Cancer. 2017;86:217–225. doi:10.1016/j.ejca.2017.09.01029031170

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