Of newly diagnosed patients with multiple myeloma, 12–20% present with acute renal failure caused by monoclonal free light chains (FLCs). Plasma exchange can reduce the pre-renal load of FLCs but randomised controlled trials have shown no clinical benefit. This disappointing outcome can be explained by the low efficiency of the procedure. A model of FLC production, distribution and metabolism in myeloma patients indicated that plasma exchange might remove only 5–10% of the total body FLCs over a three-week period. To improve removal rates we have used prolonged hemodialysis with a protein leaking dialyser. In-vitro studies indicated that the Gambro HCO 1100 dialyser, with pores of 100kDa, was the most efficient of seven tested. This dialyser was used in 10 patients with myeloma and renal failure, as part of their hemodialysis treatment, to assess FLC removal efficiency. Three of the patients were studied at initial clinical presentation with biopsy proven FLC cast nephropathy. Routine chemotherapy was used, together with prolonged daily hemodialysis and multiple measurements of FLCs in serum, urine and dialysate fluid. Serum FLCs were reduced by 40 to 70% within one hour then reduction slowed as extravascular re-equilibration occurred. FLC concentrations rebounded on successive days until chemotherapy was effective. 1.5kg of FLCs was removed from one patient over 6 weeks and another became independent of dialysis. Prolonged hemodialysis allowed removal of 5–10 times more FLCs than plasma exchange without attendant clotting problems and removal of many serum proteins (Figure 1). Proof of clinical value will require further studies. Simulations of aFLC removal by plasma exchange versus hemodialysis on the Gambro HCO 1100. Simulations: 1) 100% tumor kill on day one with only reniculoendothetial removal; 2) 10% tumor kill per day reniculoendothetial removal alone; 3) 10% tumor kill per day with plasma exchange (3.5 liters exchange in 1.5 hrs × 6 over 10 days); 4) 10% tumor kill per day with hemodialysis for 4 hours, 3 times a week; 5) 10% tumor kill per day with hemodialysis for 4 hours per day; 6) 10% tumor kill per day with hemodialysis for 12 hours per day; 7) No tumor kill with 8 hours hemodialysis on alternate days 8) No tumor kill with no direct removal. Simulations of aFLC removal by plasma exchange versus hemodialysis on the Gambro HCO 1100. Simulations: 1) 100% tumor kill on day one with only reniculoendothetial removal; 2) 10% tumor kill per day reniculoendothetial removal alone; 3) 10% tumor kill per day with plasma exchange (3.5 liters exchange in 1.5 hrs × 6 over 10 days); 4) 10% tumor kill per day with hemodialysis for 4 hours, 3 times a week; 5) 10% tumor kill per day with hemodialysis for 4 hours per day; 6) 10% tumor kill per day with hemodialysis for 12 hours per day; 7) No tumor kill with 8 hours hemodialysis on alternate days 8) No tumor kill with no direct removal.

Pulmonary drug disposition after inhalation is complex involving mechanisms, such as regional drug deposition, dissolution, and mucociliary clearance. This study aimed to develop a systems pharmacology approach to mechanistically describe lung disposition in rats and thereby provide an integrated understanding of the system. When drug‐ and formulation‐specific properties for the poorly soluble drug fluticasone propionate were fed into the model, it proved predictive of the pharmacokinetics and receptor occupancy after intravenous administration and nose‐only inhalation. As the model clearly distinguishes among drug‐specific, formulation‐specific, and system‐specific properties, it was possible to identify key determinants of pulmonary selectivity of receptor occupancy of inhaled drugs: slow particle dissolution and slow drug‐receptor dissociation. Hence, it enables assessment of factors for lung targeting, including molecular properties, formulation, as well as the physiology of the animal species, thereby providing a general framework for rational drug design and facilitated translation of lung targeting from animal to man.

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