Table 2.
Overview of studies assessing the pharmacokinetics of anticancer drugs in elderly patients.
| Author | Year | Treatment | Dose | Indication | N | Age (Mean, Range) | Patient Groups | Outcome (Elderly vs. Non-Elderly) | Comments |
|---|---|---|---|---|---|---|---|---|---|
| Yamamoto | 2000 | Docetaxel | 60 mg/m2 | NSCLC | 29 | 58 (32–76) | NA | SIG | |
| Bruno | 2001 | Docetaxel | 75–100 mg/m2 | Solid tumors | 601 | 56 (38–71) § | NA | SIG | Estimated decrease in CL at age 71 years was 7%; reported to be not clinically relevant |
| Minami | 2004 | Docetaxel w/cisplatin | Docetaxel: | NSCLC | 50 | 76 (75–86) | Docetaxel: | Docetaxel: | Elderly received a lower doxorubicin dose per protocol, resulting in a significantly lower AUC, with no difference in CL. |
| ≥75 y; n = 25 | CL: −0.7% | ||||||||
| ≥75 y: 20 mg/m2 | Vd: −22% | ||||||||
| <75 y: 35 mg/m2 | AUC: −44% * | ||||||||
| Cisplatin: 25 mg/m2 | <75 y; n = 25 | ||||||||
| 56 (39–73) | Cisplatin: | Cisplatin: | |||||||
| ≥75 y; n = 24 | CL: −6% | ||||||||
| Vd: +7% | |||||||||
| AUC: +3% | |||||||||
| <75 y; n = 27 | |||||||||
| Slaviero | 2004 | Docetaxel | 40 mg/m2 | Solid tumors | 54 | 63 (40–83) | NS | ||
| Ten Tije | 2005 | Docetaxel | 75 mg/m2 | Solid tumors | 40 | 71 (65–80) | ≥65 y; n = 20 | Cmax: −15% | |
| AUC: +6% | |||||||||
| 53 (26–64) | <65 y; n = 20 | Vdss: +15% | |||||||
| T½: +13% | |||||||||
| Hurria | 2006 | Docetaxel | 35 mg/m2 | Solid tumors | 19 | 75 (66–84) | >65 y; n = 19 | NS | No control group |
| Michael | 2012 | Docetaxel | 35–75 mg/m2 | MC, NSCLC | 20 | 62 (41–77) | NA | SIG | |
| Borkowski | 1994 | Paclitaxel | 90–265 mg/m2 | Solid tumors | 16 | 53 (38–72) | NA | NS | |
| Huizing | 1997 | Paclitaxel–carboplatin | Paclitaxel: 100–250 mg/m2 | NSCLC | 55 | 56 (38–74) | NA | Paclitaxel and carboplatin: SIG | Exclusion of patients aged ≥75 y |
| Carboplatin: 300–400 mg/m2 | |||||||||
| Nakamura | 2000 | Paclitaxel | 210 mg/m2 | NSCLC | 14 | NA | ≥70 y; n = 3 | Cmax: −8% | |
| AUC: −0.5% | |||||||||
| MRT: +8% | |||||||||
| <70 y; n = 11 | T ½: +14% | ||||||||
| CL: +4% | |||||||||
| D > 0.1 μM: +0.9% | |||||||||
| Fidias | 2001 | Paclitaxel | 90 mg/m2 | NSCLC | 13 | 76 (70–85) | ≥70 y; n = 13 | NS | No control group |
| Smorenburg | 2003 | Paclitaxel | ≥70 y: 80 mg/m2 | MC | 23 | NA (22–84) | ≥70 y; n = 8 | Unbound paclitaxel: | |
| Cmax: +40% | |||||||||
| <70 y: 100 mg/m2 | AUC: +49% | ||||||||
| <70 y; n = 15 | CL: −50% * | ||||||||
| Vss: −57% * | |||||||||
| T ½: −17% | |||||||||
| Total paclitaxel: | |||||||||
| Cmax: −5% | |||||||||
| AUC: +16% | |||||||||
| CL: −20% * | |||||||||
| Lichtman | 2006 | Paclitaxel | 175 mg/m2 | Non-hematological malignancies | 122 | NA (55–86) | 55–64 y; n = 46 | ≥65 y: | |
| 65–74 y; n = 44 | AUC: +29% | ||||||||
| CL: −21% | |||||||||
| 75–86 y; n = 32 | |||||||||
| ≥75 y: | |||||||||
| AUC: +30% | |||||||||
| CL: −19% | |||||||||
| Joerger | 2006 | Paclitaxel | 100–250 mg/m2 | Solid tumors | 168 | 56 (33–86) | NA | VMel: −5% per 10-y increase in age * | |
| Joerger | 2012 | Paclitaxel | 76–311 mg/m2 | Solid tumors | 273 | 56 (33–75) | ≥70 y; n = 19 | VMel: −13% per 10-y increase in age * | |
| <70 y; n = 254 | |||||||||
| Robert | 1983 | Doxorubicin | 12.5–50 mg/m2 | MC, lymphoma, others | 37 | 51 (17–74) | NA | ≥70 y: | Also reported that doxorubicin CL of the distribution phase was significantly influenced by aging in 26 patients studied by Piazza et al. |
| CL of distribution phase: −30% * | |||||||||
| Total CL: −23% | |||||||||
| Dobbs | 1995 | Doxorubicin | <25 m–100 mg/m2 | MC, lymphoma, others | 27 | 54 (27–75) | NA | NS | |
| Dees | 2000 | Doxorubicin–cyclophosphamide | Doxorubicin: 60 mg/m2 | MC | 14 | NA (35–79) | ≥65 y; n = 7 | NS | Increasing age (continuous) was weakly correlated with Vdss, but not with CL; no significance was reached with age as a categorical variable |
| Cyclophosphamide: 600 mg/m2 | |||||||||
| <65 y; n = 7 | |||||||||
| Li | 2003 | Doxorubicin | 30–75 mg/m2 | MC, lymphoma, sarcoma, others | 56 | 50 (12–74) | NA | SIG | |
| Joerger | 2007 | Doxorubicin–cyclophosphamide | Doxorubicin: 60 mg/m2 | MC | 65 | 56 (29–81) | NA | Doxorubicin: CL: −9% per 10-y increase of age * | |
| Cyclophosphamide: NS | |||||||||
| Cyclophosphamide: 600 mg/m2 | |||||||||
| Jakobsen | 1991 | Epirubicin | 40–135 mg/m2 | MC | 78 | NA (31–74) | NA | NS | |
| Wade | 1992 | Epirubicin | 25–100 mg/m2 | MC, lymphoma, sarcoma | 36 | NA (20–73) | ≥70 y; n = 1 | SIG | Significant in women only, no elderly men were included. |
| <70 y; n = 35 | |||||||||
| Predicted CL: −34% (70 vs. 25 y) | |||||||||
| Eksborg | 1992 | Epirubicin | 60 mg/m2 | MC | 66 | 61 (36–78) | NA | SIG | |
| Sorio | 1997 | Vinorelbine (iv) | 30 mg/m2 | MC | 10 | 72 (66–81) | ≥66 y; n = 10 | NS | No control group |
| Gauvin | 2000 | Vinorelbine (iv) | 20–30 mg/m2 | Solid tumors | 12 | 74 (66–79) | ≥66 y; n = 12 | SIG | No control group |
| Gauvin | 2002 | Vinorelbine (iv) | 20–30 mg/m2 | Solid tumors | 27 | NA (66–79) | ≥66 y; n = 27 | SIG | No control group |
| ECOG 0–3 | |||||||||
| Variol | 2002 | Vinorelbine (iv/po) | Vinorelbine (iv): 20–45 mg/m2 | Solid tumors | iv: 64 | iv: 55 (27–72) | NA | NS | iv same as Nguyen: 3 phase I studies |
| Vinorelbine (po): 60–100 mg/m2 | po: 175 | po: 57 (21–77) | |||||||
| Nguyen | 2002 | Vinorelbine (iv) | 20–45 mg/m2 | Solid tumors | 64 | 55 (27–73) | NA | NS | 3 phase I studies |
| Lush | 2005 | Vinorelbine (iv) | 30 mg/m2 | Solid tumors | 20 | 57 (40–74) | ≥65 y; n = 14 | Cmax: +26% | Age mean (range) for total group of 27 pts, of which 20 received iv vinorelbine |
| T ½: +6% | |||||||||
| <65 y; n = 6 | |||||||||
| AUC: +30% | |||||||||
| CL: −17% | |||||||||
| Wong | 2006 | Vinorelbine (iv) | Flat dose: 60 mg | Solid tumors | 34 | 63 (43–81) | NA | NS | Age mean (range) for total group of 43 pts, of which 34 pts were included for PK analysis |
| Puozzo | 2004 | Vinorelbine (po) | 60 mg/m2 | Solid tumors | 48 | 74 (70–82) | ≥70 y; n = 48 | AUC: +11% | Phase II including elderly compared w/phase I reference population; same population as Gridelli et al. |
| Phase I <70 y population: 56 (31–82); n = 52 | Cmax: +10% | ||||||||
| CL: −2% | |||||||||
| T ½: +7% | |||||||||
| Gridelli | 2006 | Vinorelbine (po) | 60 mg/m2, after 3 cycles: 80 mg/m2 | NSCLC | 48 | 74 (70–82) * | ≥70 y; n = 48 | NS | No control group; age mean (range) for total group of 56 patients, of which 48 pts were included for PK analysis (not mentioned in Puozzo et al.) |
| Port | 1991 | 5-FU | 320–960 mg/m2 | Solid tumors | 26 | 53 (43–75) | NA | CL: −16% (70 y vs. 50 y) | |
| Milano | 1992 | 5-FU | 365–1224 mg/m2 | Squamous cell carcinoma of head and neck | 360 | 62 (25–91) | >70 y: n = 58 | NS | Only 5 elderly women included |
| 51–70 y: n = 245 | |||||||||
| ≤50 y: n = 57 | |||||||||
| Denham | 1999 | 5-FU–cisplatin | 5-FU: 800 mg/m2 | Esophageal cancer | 44 | 72 (42–91) | NA | 5FU: SIG | |
| Cisplatin: 80 mg/m2 | |||||||||
| Duffour | 2010 | 5-FU | NA | CRC | 103 | ≥65 y: 70 (65–80) | ≥65 y: n = 48 | Cycle 1: | |
| CL: −3% | |||||||||
| <65 y: 59 (33–64) | <65 y: n = 55 | Vd: −8% | |||||||
| T ½: −4% | |||||||||
| AUC: 0.5% | |||||||||
| Cycle 2: | |||||||||
| AUC: 10% | |||||||||
| Mueller | 2013 | 5-FU | 400 mg/m2 bolus, followed by 2400 mg/m2 ** | Solid tumors | 31 | 63 (31–81) | ≥65 y: n = 14 | NS | |
| <65 y: n = 17 | |||||||||
| Cassidy | 1999 | Capecitabine | Flat dose: 2000 mg | Solid tumors | 25 | 63 (41–80) | NA | NS | Bioequivalence study of two tablet formulations |
| Louie | 2013 | Capecitabine | 1000 mg/m2 | CRC | 29 | ≥70 y: 77 ± 5 | ≥70 y: n = 24 | Capecitabine: | |
| Cmax: +200% * | |||||||||
| T ½: +5% | |||||||||
| AUC: +150% * | |||||||||
| CL: −71% * | |||||||||
| <60 y: 55 ± 3 | <60 y: n = 5 | Vd: −74% * | |||||||
| 5-FU: | |||||||||
| Cmax: −23% | |||||||||
| T ½: −10% | |||||||||
| AUC: −26% | |||||||||
| Daher Abdi | 2014 | Capecitabine | 1250–2300 mg/m2 | MC, CRC | 20 + 40 | ≥75 y: 81 (75–92) | ≥70 y: n = 20 | NS | PK data of 40 patients <75 y from 2 previous phase I trials |
| <75 y: 55 (30–73) | <75 y: n = 40 | ||||||||
| Merino-Sanjuan | 2011 | Carboplatin–gemcitabine | Carboplatin: | NSCLC | 24 | ≥70 y: 77 (71–81) | NA | Carboplatin: CL: −31% * | Age mean (range) for total group of 33 pts, of which 24 pts were included for PK analysis |
| ≥70 y: AUC 4 vs. | |||||||||
| <70 y: 58 (44–66) § | |||||||||
| <70 y: AUC 5 | |||||||||
| Yamamoto | 1995 | Cisplatin | 80 mg/m2 | NSCLC | 23 | 61 (41–81) | >70 y: n = 8 | SIG | |
| ≤70 y: n = 15 | |||||||||
| Gupta | 2012 | Trastuzumab emtansine | 1.2–4.8 mg/kg | MC | 273 | 54 (SD 10 y) | NA | NS | 87% of pts received 3.6 mg/kg |
| Lu | 2014 | Trastuzumab emtansine | 1.2–4.8 mg/kg | MC | 671 | 53 (27–84) | >75 y: n = 16 | NS | 95% of pts received 3.6 mg/kg |
| 65–75 y; n = 78 | |||||||||
| <65 y; n = 577 | |||||||||
| Motzer | 2008 | Everolimus | Flat dose: 10 mg/day | RCC | 272 | 61 (27–85) | NA | NS | As reported in the FDA’s drug approval review |
* Significant effect, as defined in the original publication; § age median/mean (range) concerns total group of included patients in the study, of which only a part was included for PK analysis of the specific administrated treatment drug; ** as simulated using NONMEM, whereas the actual dosing range was not provided, yet was given as part of FOLFOX, FOLFIRI, 5-fluorouracil (5-FU) or FOLFIRINOX; NS = non-significant influence of aging on PK parameters, as displayed when the percentage of change of PK parameters could not be ascertained from the article, e.g., when results were presented using population PK modeling; N = patient number; SIG = significant influence of aging on PK parameters, as displayed when the percentage of change of PK parameters could not be ascertained from the article, e.g., when results were presented using population PK modeling; AUC = area under the concentration-time curve (μg/mL·h, μg/mL·min, μg/L·h or μmol/L·h); Cmax = maximum plasma concentration (μg/mL or μg/L); CL = clearance (L/h, L/min, mL/min or L/h/m2); Vss = volume of distribution at steady-state conditions; CRC = colorectal cancer; D >0.1 μM = duration drug concentration above 0.1 μM (h); ECOG = Eastern Cooperative Oncology Group score; FDA = Food and Drug Administration; iv = intravenous; MC = mamma carcinoma; MRT = mean residence time (h); NSCLC = non-small cell lung cancer; PK = pharmacokinetics; po = per os; RCC = renal cell carcinoma; SD = standard deviation; T ½ = terminal half-life (h or min); Vd = volume of distribution (L); Vdss = volume of distribution at steady state (L, or L/m2); VMel = maximal elimination capacity (μmol/h); y = year.