What are the typical doses of zinc acetate and penicillamine for treating Wilson's disease?

Dosing of Zinc Acetate and Penicillamine in Wilson's Disease

For penicillamine, start with 250-500 mg/day and titrate up by 250 mg increments every 4-7 days to a maximum of 1000-1500 mg/day in 2-4 divided doses, with maintenance typically at 750-1000 mg/day; for zinc acetate, use 150 mg elemental zinc daily in three divided doses for adults and children >50 kg, or 75 mg/day in three divided doses for children <50 kg, taken 30 minutes before meals. 1, 2

Penicillamine Dosing

Initial Dosing Strategy

• Begin with incremental dosing of 125-250 mg/day (or 250-500 mg/day), increased by 250 mg increments every 4-7 days to minimize early sensitivity reactions 1
• Target dose: 1000-1500 mg/day divided into 2-4 doses 1
• Never exceed 1500 mg/day at once, as this can lead to rapid and often irreversible neurological deterioration 1

Maintenance Dosing

• Adults: 750-1000 mg/day in 2 divided doses 1
• Children: 20 mg/kg/day rounded to nearest 250 mg, given in 2-3 divided doses 1

Administration Timing

• Take 1 hour before or 2 hours after meals to maximize absorption, as food reduces absorption by approximately 50% 1
• Closer proximity to meals is acceptable if it ensures compliance 1
• Require pyridoxine supplementation at 25-50 mg daily 1

Critical Warnings

• 20-30% of patients develop severe side effects requiring discontinuation 1
• Neurological worsening occurs in 10-50% of patients during initial treatment, with one recent series showing 13.8% adversely affected 1
• Immediate discontinuation required for: early sensitivity reactions (fever, rash, lymphadenopathy, neutropenia, thrombocytopenia, proteinuria within 1-3 weeks), nephrotoxicity, severe bone marrow toxicity 1

Zinc Acetate Dosing

Standard Dosing

• Adults and children >50 kg: 150 mg elemental zinc daily in three divided doses (50 mg three times daily) 3, 2
• Children <50 kg: 75 mg elemental zinc daily in three divided doses (25 mg three times daily) 3, 2
• Minimum effective daily dose is 75 mg, which must be divided into at least two doses to be effective 4

Administration Timing

• Take 30 minutes before meals to maximize absorption 3, 5, 2
• In rare cases of gastric intolerance with morning dose, may take between breakfast and lunch 2
• Capsules must be swallowed whole, not opened or chewed 2

Important Limitations

• Not recommended for initial therapy of symptomatic patients due to delayed onset of action from zinc-induced metallothionein synthesis 2
• Symptomatic patients should be treated initially with chelating agents, then transitioned to zinc for maintenance once clinically stable 2

Monitoring Parameters

For Penicillamine

• 24-hour urinary copper excretion: should be 200-500 μg (3-8 μmol) per day on treatment 1
• Non-ceruloplasmin-bound copper: should normalize with effective treatment 1
• Regular monitoring for proteinuria, hematuria, CBC for bone marrow toxicity 1

For Zinc Acetate

• 24-hour urinary copper excretion: should be <125 μg (<2 μmol) per 24 hours on stable treatment 1, 2
• Non-ceruloplasmin plasma copper: keep below 20 μg/dL 2
• Urinary zinc levels may be measured to check compliance 1
• Monitor serum zinc levels and alkaline phosphatase periodically 5

Drug Interactions and Special Considerations

Critical Interaction

• If using both zinc and copper chelators, separate dosing by 5-6 hours to avoid neutralization of efficacy 3
• Zinc chelates iron; avoid coadministration with iron supplements 1

Pregnancy Considerations

• For penicillamine in Wilson's disease during pregnancy: limit to 750 mg/day; reduce to 250 mg/day for last 6 weeks if cesarean section planned 6
• Zinc acetate appears safer in pregnancy than penicillamine, though zinc does appear in breast milk and may cause copper deficiency in nursing infants 2, 6

Comparative Safety

• Recent meta-analysis shows zinc salts have lower incidence of adverse effects (RR: 2.42 for penicillamine vs zinc, p=0.014) and lower neurological deterioration (RR: 1.96 for penicillamine vs zinc, p=0.001) compared to penicillamine 7
• For neurological Wilson's disease specifically, zinc may be preferable as initial therapy given lower risk of neurological worsening 1, 7